==== Front Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 10.3390/ijms21239317 ijms-21-09317 Review Airway Redox Homeostasis and Inflammation Gone Awry: From Molecular Pathogenesis to Emerging Therapeutics in Respiratory Pathology Checa Javier https://orcid.org/0000-0003-2827-9392Aran Josep M. * Immune-Inflammatory Processes and Gene Therapeutics Group, IDIBELL, L’Hospitalet de Llobregat, 08908 Barcelona, Spain; jcheca@idibell.cat * Correspondence: jaran@idibell.cat; Tel.: +34-93-2607428; Fax: +34-93-2607414 07 12 2020 12 2020 21 23 931720 11 2020 05 12 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).As aerobic organisms, we are continuously and throughout our lifetime subjected to an oxidizing atmosphere and, most often, to environmental threats. The lung is the internal organ most highly exposed to this milieu. Therefore, it has evolved to confront both oxidative stress induced by reactive oxygen species (ROS) and a variety of pollutants, pathogens, and allergens that promote inflammation and can harm the airways to different degrees. Indeed, an excess of ROS, generated intrinsically or from external sources, can imprint direct damage to key structural cell components (nucleic acids, sugars, lipids, and proteins) and indirectly perturb ROS-mediated signaling in lung epithelia, impairing its homeostasis. These early events complemented with efficient recognition of pathogen- or damage-associated recognition patterns by the airway resident cells alert the immune system, which mounts an inflammatory response to remove the hazards, including collateral dead cells and cellular debris, in an attempt to return to homeostatic conditions. Thus, any major or chronic dysregulation of the redox balance, the air–liquid interface, or defects in epithelial proteins impairing mucociliary clearance or other defense systems may lead to airway damage. Here, we review our understanding of the key role of oxidative stress and inflammation in respiratory pathology, and extensively report current and future trends in antioxidant and anti-inflammatory treatments focusing on the following major acute and chronic lung diseases: acute lung injury/respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and cystic fibrosis. oxidative stressinflammationrespiratory diseasestherapeutic strategies ==== Body 1. Introduction Due to its continuously exposed surface to the external environment, the lung exhibits a formidable defense system constituted by a high number of interacting mechanisms [1,2]. First, anatomical retention features such as the nasopharyngeal barrier filter particles or microorganisms higher than 2–3 µm [3,4,5]. Secondly, there are systems to expel the external elements, i.e., the cough [6], and the mucociliary system [7]. Whether or not the external and potentially harmful particles overcome these mechanisms, the humoral factors come into play, including bactericidal and antiviral secretions (mucins, defensins, lactoferrin, complement factors, etc.) [8,9], and cellular factors of the innate [10] and adaptive immune system. These include the airway epithelial cells [11]; the phagocytic cells that, in turn, comprise polymorphonuclear (PMN) cells such as neutrophils (the most abundant immune cell type) [12] or eosinophils [13]; monocytes and macrophages [14,15]; natural killer cells (NKC) [16]; mastocytes [17]; and dendritic cells [18]. All these cells recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) through pattern recognition receptors (PRRs) [19], and Toll-like receptors (TLR) are the most studied [20]. Their stimulation triggers the activation of antimicrobial genes and inflammatory cytokines and chemokines, as well as the direct response against antigens [21], activating the adaptive immune system, namely B and T lymphocytes [22,23]. Nevertheless, when one or several components of this intricate network of pulmonary defense mechanisms fail, homeostasis is disrupted, and respiratory pathology ensues causing oxidative stress and inflammation. This review briefly underscores the molecular mechanisms behind environmental stress (airborne pollutants, pathogens, and allergens) causing pulmonary immune-inflammatory responses and focuses on current pharmacological options, emerging, and promising therapeutic approaches and new investigational treatments targeting the most common acute and chronic respiratory illnesses. 2. Reactive Oxygen Species Production in the Airways Environmental pollutants such as ozone (O3) and nitrogen dioxide (NO2) react with several molecules at the respiratory surface and generate secondary reactive oxygen species (ROS) such as superoxide radicals (O2·−), hydrogen peroxide (H2O2), and hydroxyl radicals (OH·) [24,25]. Additionally, lung cells generate ROS as by-products of aerobic metabolism involving enzymatic reactions in the mitochondrial electron transport chain (e.g., through activity of amine oxidases, α-ketoglutarate dehydrogenase (α-KGDH), and pyruvate dehydrogenase (PDH), and activation of the p66shc adaptor protein) [26,27,28]. Furthermore, ROS can be produced in peroxisomes [29], or by cytochrome P450 enzymes, cyclooxygenases, and lipoxygenases [30]. Nitric oxidase synthases (NOS) expand the spectrum of ROS producing reactive nitrogen species (NO2 or ONOO−) [31]. ROS are also produced as mediators of biological functions, with a role in inflammatory processes involving epithelial and endothelial cells, alveolar macrophages, and granulocytes [32,33]. NADPH oxidases (NOX) enzymes are involved in both bacterial killing and regulation of inflammatory mediators [34]. Indeed, dual oxidases, DUOX1 and DUOX2, the major isoform of NOX, are expressed preferentially in the respiratory epithelium [35,36,37]. 3. Respiratory Surface: Antioxidant Defenses The air–liquid interface covering the developed airways is an environment subjected to continuous oxidative stress. Accordingly, the respiratory epithelium is exposed to endogenous and also to environmental ROS. Therefore, it expresses a variety of antioxidant enzymes. Superoxide dismutases such as SOD3 (an extracellular SOD, EC-SOD) [38,39,40], highly-expressed in the lung at the extracellular matrix and at the cell surfaces [41], generate H2O2 which is detoxified by other enzymes. Catalase, decomposes H2O2 into H2O and O2, predominantly within alveolar macrophages and type II epithelial cells [42,43]. Glutathione (GSH) peroxidase (GPX) catalyzes the reduction of H2O2 or other peroxides to glutathione disulfide (GSSG) and H2O, of which GPX1 is thought to be responsible for 95% of overall lung tissue GPX activity [44]. Peroxiredoxins (PRX), with all six mammalian family members expressed in different compartments within the lung [45], particularly PRX I, III, V, and VI in the bronchial epithelium, PRX V and VI in the alveolar epithelium, and PRX I and III in alveolar macrophages, decompose H2O2 and protect against oxidative stress [46,47,48]. Thioredoxin (TRX), whose main antioxidant role is related to its ability to regenerate oxidized forms of PRX [49,50], catalyzes the reduction of disulfide bonds, modulates signal transduction pathways, and has anti-inflammatory properties [51,52]. Finally, glutaredoxins (GRX) participate in the reduction of oxidative modifications involving GSH [53,54]. The following small non-enzymatic low-molecular-weight antioxidant molecules are highly relevant: ascorbic acid (vitamin C) [55], uric acid [56], GSH [57,58], and α-tocopherol (vitamin E) [59]. These non-enzymatic molecules are the most prominent antioxidants reacting with reactive oxidant gases such as O3 and NO2 [60,61,62,63] and with the secondary oxidants generated by them, which can increase the oxidative injury [64]. Furthermore, the enzymatic antioxidants complement the function of these small molecules. Nuclear factor erythroid 2-related factor (Nrf2) regulates the transcription of both antioxidant genes coding for many of the above-highlighted enzymes and phase II detoxification genes [65,66,67,68]. 4. Inflammation and Oxidative Stress in Pulmonary Diseases A variety of immune and non-immune cells are activated during an inflammatory process. Each cell type releases cytokines and mediators that modify the activities of other cells, inducing an inflammatory network that progresses and resolves towards healthy homeostatic, or pathological outcomes. The lung is a vital organ for gas exchange and is constantly exposed to harmful airborne pathogens. Therefore, an immediate and intense protective/defensive inflammatory action is required to eliminate the invaders as early as possible. Nevertheless, excessive inflammation can be life threatening [1]. Consequently, a delicate balance between inflammation and anti-inflammation is essential for lung homeostasis and for the prevention of chronic inflammation [69]. Among the main inflammatory mediators involved in the pathogenesis of respiratory diseases are biochemical mediators such as histamine, thrombin, complement anaphylatoxins, prostaglandins, nitric oxide (NO), and molecules induced by oxidative stress [70]. These compounds mediate cell signaling and enhance cytokine production, among other activities. Thus, airborne toxicants stimulate local ROS production inducing protein oxidation, lipoxidation, glycation end products, and DNA damage, and leading to mitochondrial dysfunction, cell death, the recruitment of inflammatory cells (mainly macrophages and neutrophils), profibrotic changes or mucus hypersecretion. These oxidative stress-mediated cellular processes drive the development of key environmental respiratory diseases such as acute lung injury/respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis, and affect the progression of the most common hereditary disease affecting the lung, i.e., cystic fibrosis. 4.1. Acute Pulmonary Inflammation Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) and its milder form acute lung injury (ALI) are critical pulmonary dysfunctions caused by heterogeneous pathologic factors [71] involving acute development of respiratory failure and severe hypoxemia [72,73,74], bilateral diffuse lung infiltrations, and impaired alveolar liquid clearance [75]. Lung injury leads to pulmonary vascular permeability, increased production of proinflammatory factors and enhanced expression of the adhesion molecules necessary for leukocyte recruitment and neutrophil migration across the endothelial layer [76,77]. Activated neutrophils secrete cytotoxic agents such as granular enzymes, proinflammatory cytokines, bioactive lipids, and along with epithelium and endothelium, excessive ROS [78], which upregulate the expression of proinflammatory cytokines and adhesion molecules amplifying the tissue damage and pulmonary edema [79,80]. Furthermore, a priority upon initiation of mechanical ventilation for ALI patients is providing them 100% FiO2 (fraction of inspired oxygen). Nevertheless, protecting against hypoxemia may predispose to oxidative stress, which may be further enhanced by decreased levels of GSH [81]. ARDS treatment has not experienced significant advances in the last 50 years. Early detection is the best approach to attenuate the development of ALI/ARDS. Therefore, several imaging techniques (ultrasound, CT scan, and positron emission tomography) are being assessed for the diagnosis of capillary permeability edema in early phase ARDS, indicative of damage to the alveolar-capillary membrane, given the poor sensitivity of chest X-rays [82,83,84,85,86]. There is no efficient therapy available, although mechanical lung ventilation has long been applied as a supportive approach for healing lung oxygenation, supplemented by anti-inflammatory drugs. Corticosteroid therapy was first indicated for ARDS by Ashbaugh and colleagues [73]. Indeed, despite its relevant side effects, low-dose and extended steroid treatment seems to improve pulmonary physiology in ARDS patients [87]. Other traditional treatments are fluid and hemodynamic management [88] to decrease pulmonary edema. The objective is to maintain the lowest intravascular volume. 4.2. Chronic Pulmonary Inflammation 4.2.1. Asthma Asthma is a chronic inflammatory disorder of the airways in which gene–environment interactions involving a variety of cell types play an important role [89,90], although its overall pathogenesis remains unknown. The inflammatory response in asthma consists of the recognition of allergen patterns by TLRs [91]. Most asthmatics have type 2 inflammation, related to the presence of type 2 cytokines (interleukins IL-4, IL-5, and IL-14) and a variety of inflammatory cells (eosinophils, mast cells, basophils, type 2 T helper (Th2) lymphocytes, immunoglobulin E (IgE)-producing plasma cells, epithelial cells, and macrophages) [92]. Myeloid dendritic cells process allergens and release chemokine (C-C motif) ligands CCL17 and CCL22 to attract Th2 cells to the injured region [93]. IgE molecules sensitize mast cells to release cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2) [94]. Damaged epithelial cells release CCL11 to recruit eosinophils, which attract more proinflammatory mediators [95]. Eosinophils also produce pro-resolving lipid mediators (PD1) and these stimulate IL-10 production and macrophage phagocytosis, promoting the resolution of inflammation [96]. Damaged epithelial cells release stem cell factor (SCF) to activate myofibroblasts to repair damaged epithelial cells. Airway epithelial cells also play a relevant role regulating type 2 inflammation via cytokines (IL-25, IL-33, and thymic stromal lymphopoietin) [92]. Oxidative stress is important in asthma [97,98]. Steroid therapy attenuates H2O2 [99], oxidative stress markers [100] and NO levels [101]. An increase in ROS production is inversely correlated with forced expiratory volume in 1 s (FEV1) [102]. Therefore, inflammation in asthma results in increased oxidative stress in the airways [103], in alveolar macrophages, and in eosinophils and neutrophils [104], associated with damage to a wide range of biologic molecules such as lipids and proteins [105,106]. Numerous cytokines such as tumor necrosis factor alpha (TNF-α), heparin-binding epidermal growth factor (HB-EGF), fibroblast growth factor 2 (FGF2), angiotensin II (AII), serotonin, and thrombin are found in the lung during inflammation and activate oxidases that lead to increased ROS in cell culture [107]. ROS decrease β-adrenergic function in the lung [108] and, consequently, airway hyperresponsiveness is produced by increasing the vagal tone due to damage to oxidant-sensitive beta-adrenergic receptors [109]. ROS also sensitize airway muscles to acetylcholine-induced contraction [110,111] and produce bronchial hyperactivity [112], promote histamine release from mast cells, and increase mucus secretion from airway epithelial cells [113]. Furthermore, ROS prompt endothelial barrier dysfunction through tight junctions disruption, which increases the permeability to fluid, inflammatory cells, and mediators [114,115], decrease numbers and function of epithelial cilia [116], and stimulate mucin secretion [117]. In addition, H2O2 activates mitogen-activated kinases (MAPKs) in tracheal myocytes [118] and stimulates the tracheal smooth muscle to contract [119,120,121]. Regarding antioxidant defenses, despite increased levels of GSH in the airways, the ratio of oxidized to reduced GSH also increases [57]. Other antioxidants such as ascorbate and alpha-tocopherol decrease [122,123], and SOD activity, but not SOD quantity [39], is likewise diminished [124,125,126,127,128,129]. Catalase activity is suppressed [130,131]. GPX1 can also promote both proinflammatory cytokine production and neutrophilia in response to LPS challenge [132], and ovalbumin-induced allergic asthma. In fact, GPX1 regulates T helper cell proliferation and differentiation toward Th2 and Th17 phenotypes [133]. Likewise, GPX3 is elevated in asthmatic airways through oxidant-induced activation of activator protein 1 (AP-1) [134,135]. Increased extracellular levels of TRX have been reported as well [136,137], indicating increased oxidative stress [49]. Lung tissue expression of GRX-1 is increased in models of allergic asthma [138,139]. Several reports have shown that GRX-1 mediates proinflammatory signaling in LPS-mediated lung inflammation or during allergic airways disease, possibly by regulating S-glutathionylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) or other proinflammatory signaling pathways [138,139,140], although its importance in regulating smoking-induced lung inflammation and injury is less clear [141,142,143]. Additionally, during the progress of chronic pulmonary diseases such as chronic obstructive pulmonary disease (COPD) or asthma, alteration of the redox homeostasis leads to dysregulation of Nrf2 and defective antioxidant signaling [144,145,146]. Considering treatments, among the traditional treatments are inhaled corticosteroids (ICS) [147,148]. These reduce inflammation by modulating NF-кB and AP-1 expression, and are effective preventing oxidative stress [149,150]. In new onset untreated persistent asthma, low-dose inhaled budesonide reduces asthma exacerbations by almost 50% [151], and ICS can reduce the number of airway eosinophils [152,153,154]. A combination of ICS and long-acting β2-agonists (LABAs) (e.g., budesonide and formoterol) significantly reduces asthma exacerbations compared with ICS alone [155]. Alternative treatments are antileukotrienes [156], the anticholinergic tiotropium [157], and environmental control [158]. Nevertheless, even in patients with well controlled asthma, exacerbations occur. Inhaled or nebulized short-acting β2-agonists (SABAs), such as albuterol or levalbuterol, provide rapid relief of symptomatic asthma [159]. Adding the short-acting anticholinergic ipratropium bromide to the inhaled SABA albuterol in severe exacerbations improves lung function and decreases rates of hospitalization [159,160,161]. Moreover, several studies have assessed ICS and oral corticosteroids (OCS) during moderate or severe acute asthma exacerbations. However, the evidence for the efficacy of these agents remains controversial because of significant safety concerns and weak outcomes [148,162,163]. 4.2.2. Chronic Obstructive Pulmonary Disease (COPD) COPD is mainly initiated by inhalation of cigarette smoke, which induces oxidative damage to lung epithelial cells, leading to the development of a chronic persistent inflammatory response from the peripheral airways to the lung parenchyma [164]. Cigarette pollutants, through PRRs such as TLRs and purinergic receptors, and damage-associated molecular patterns (DAMPs) released by apoptotic or necrotic cells, readily initiate pattern recognition [165]. This is followed by the local buildup of chemotactic factors, which attract inflammatory cells to the injured region [166,167,168]. Macrophages, epithelial cells, and infiltrated inflammatory cells release, on the one hand, proteases such as matrix metalloproteinase 9 (MMP9), resulting in elastin degradation and emphysema [169,170]. Thereby the immune system switches to a Th17 response to promote inflammation [171,172] and, on the other hand, also secretes transforming growth factor-β (TGF-β), a pleiotropic cytokine that triggers tissue remodeling and fibrosis [173,174]. Furthermore, the airway smooth muscle produces inflammatory cytokines, proteases, and growth factors, which are essential in the remodeling process and induce structural and functional changes in the airways [175]. ROS directly damage biological molecules and lung extracellular matrix, leading to cell dysfunction or death, and activate NF-κB, which enhances the expression of inflammatory genes such as IL-8 and TNF-α, important in COPD, contributing to reversible airway narrowing [176]. Neutrophils show increased oxide anion (O2−) levels [177], and lipid peroxidation products such as thiobarbituric acid (TBA), linoleic acid (LA), and F2-isoprostane are also increased [178]. Conversely, the plasma antioxidant capacity is decreased [179]. Oxidative stress contributes to a proteinase–anti-proteinase imbalance, both by inactivating anti-proteinases such as α1-antitrypsin (A1AT) and secretory leukocyte proteinase inhibitor, and by activating MMPs [180,181]. As occurs in asthma, GSH levels are decreased and hold a more oxidized state [182]. In contrast, lung SOD2 levels are increased in response to hyperoxia and inflammatory cytokines [183]. Genetic studies have shown that SOD3 is associated with lung function and the development of COPD [184,185,186]. TRX may be reduced in COPD [187]. Increased levels of extracellular GRX-1 have also been reported in the lung and sputum of asthma and COPD patients [139,188], although its relevance regulating smoking-induced lung inflammation and injury is still unclear [141,142]. Likewise, induction of Nrf2-mediated antioxidant gene expression seems to be flawed [144,189]. Historical treatments for COPD have primarily focused on long-term oxygen therapy and restoring pulmonary function by tackling the underlying inflammation and bronchoconstriction causing air flow obstruction (shortness of breath, cough, chest tightness, and mucus production) [190]. Guidelines recommend the use of long-acting bronchodilators such as LABAs, with or without ICS, or long-acting anticholinergics, and, in severe exacerbations, the addition of phosphodiesterase inhibitors, including roflumilast [191]. Oral corticosteroids are often used in patients that fail to respond to these therapies. 4.2.3. Pulmonary Fibrosis Pulmonary fibrosis is the outcome of a diverse group of lung insults including toxins, fibers/particles, autoimmune reactions, drugs, and radiation. Nevertheless its primary etiology is unknown and in most cases is referred to as idiopathic pulmonary fibrosis (IPF) [192]. Aberrant epithelial-mesenchymal crosstalk is the main hallmark of IPF, although the immune-inflammatory process plays an important role in all stages of fibrosis. Neutrophil accumulation is a characteristic feature of alveolitis [193,194], leading to persistent injury, tissue remodeling and fibrosis, possibly through the release of proteases such as elastase. Macrophages initially secrete proinflammatory cytokines and later recruit fibroblasts, epithelial and endothelial cells, participating in the reparative environment. M2 macrophages seem to play a key role regulating fibrosis [195]. In fact, the risk for IPF acute exacerbations seems to be reflected by M2 cytokine production levels [196]. Monocytes also play a key role during fibrogenesis; they serve as precursor cells for pro-fibrotic macrophages and fibrocytes [197,198], become highly activated during fibrotic conditions, and their presence correlates directly with the extent of fibrosis in the lungs [199]. Fibrocytes are circulating mesenchymal progenitor cells that contribute to fibroblast activation, extracellular matrix production, and other paracrine functions, leading to tissue remodeling and ongoing fibrosis [200,201]. Furthermore, recent studies have suggested that type 2 innate lymphoid cells (ILC2) communicate with mast cells to release mediators that are able to modulate the disease rather than its pathogenesis [202,203]. Regarding the adaptative immune system, T cells are widely present in active-disease regions and pulmonary tertiary lymphoid organs (TLOs) in patients with IPF [204,205,206]. A Th1/Th2 immune response imbalance has been considered essential in IPF pathogenesis. Certainly, Th2 cytokines promote pro-fibrotic responses, whereas Th1 cytokines (IFNγ and IL-12) may be protective [207,208,209,210,211]. Historically, it has been thought that regulatory T cells (Tregs) had a protective role in IPF because of their anti-inflammatory and anti-fibrocyte accumulation activities. Nevertheless, recent studies have indicated that the role of Tregs differed among the distinctive stages of fibrosis. Indeed, Tregs seem also to secrete pro-fibrotic cytokines [212]. Tilting the balance between oxidant production and antioxidant protection towards the former leads to ROS accumulation, which is promoted by fibrotic stimuli of unidentified origin [213,214]. In fact, oxidants may contribute to the occurrence of pulmonary fibrosis because of their effects on the secretion of cytokines and growth factors such as TGF-β [215,216]. TGF-β induces ROS production by activation of NOX (e.g., NOX4) [217,218,219] or mitochondrial dysfunction. It also reduces the expression of both catalase and SOD2, and thereby decreases natural cellular antioxidant production [220,221,222,223]. Human subjects with IPF have shown increased levels of oxidized proteins [211,224]. As in asthma and COPD, GSH levels are often suppressed and occur in a more oxidized state [225]. Animal studies in mice have demonstrated a protective role of SOD3 in models of interstitial lung disease, including bleomycin-induced pulmonary fibrosis [226,227,228,229], which have been confirmed in patients [230]. TRX expression is also upregulated in pulmonary fibrosis and interstitial lung disease [231,232]. There has been no evidence for an effect of corticosteroid treatment in patients with IPF [233]. In addition, N-acetylcysteine, either alone or with azathioprine and prednisone, offered no significant benefit and was even detrimental [234,235]. In the last years, two anti-fibrotic drugs have been introduced for IPF treatment: pirfenidone and nintedanib [236,237,238], and both decrease the progression of the disease and enhance its evolution. In severe disease, the possibility of lung transplantation should be considered [239]. For the treatment of persistent hacking cough among people with IPF, dimemorphine phosphate, codeine phosphate, prednisone, or thalidomide are indicated [240]. Low doses of morphine improve the sensation of breathlessness and cough in patients with advanced disease. Among non-pharmacological treatments, home oxygen therapy is feasible in patients with IPF and hypoxemia or respiratory rehabilitation [241]. 4.3. Cystic Fibrosis Cystic fibrosis (CF), the most frequent recessive hereditary autosomal disease in the Caucasian population, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite the occurrence of multiorgan complications in CF, respiratory failure secondary to chronic lung infection caused by recurrent bacteria and the subsequent inflammation is the most serious outcome of this condition [242,243]. Thus, abnormalities in the CFTR chloride (Cl−) channel at the airway apical surface cause the failure of Cl− secretion and, consequently, sodium (Na+) hyperabsorption in epithelial cells, dehydrating the airway surface fluid layer, and impairing mucociliary clearance [244,245,246]. These events support bacterial infection [247,248], which attracts neutrophils (the largest source of ROS) to the site of infection (Figure 1). This infection-inflammation vicious cycle leads to irreversible airway destruction and fibrosis [249]. Although neutrophils, epithelial cells, and their effectors have been most intensely studied, many other cell types, including dendritic cells, T and B lymphocytes, macrophages, and airway smooth muscle cells produce inflammatory mediators and are actively involved in the host inflammatory response in CF [250]. The DUOX/LPO system is engaged by epithelial cells to produce significant quantities of ROS (H2O2) through two isoforms of NOX expressed in their apical membrane (DUOX 1 and DUOX 2) thought to be related to the CFTR channel [37]. An important function of DUOXs is to support lactoperoxidase (LPO), which is released by caliciform cells of the airways and by the submucosal glands to generate bactericidal hypothiocyanite from thiocyanate and H2O2 [251]. This system is activated continuously and independently of the presence of an open bacterial infection, unlike NOX/MPO [252]. Multiple studies have shown the antimicrobial function of DUOX/H2O2 and LPO either against bacteria [253] or viruses [254]. Even mammalian airway epithelial cells might present a novel innate defense mechanism killing bacteria through ROS generation [255]. In CF patients, the level of NO is reduced, and this is directly related to a deterioration of the pulmonary function [256,257]. A sub-optimal antioxidant protection is observed [258]. There are other proteins regulating the H2O2 levels, such as TRX1, GSTP1, PRDX6 [259], PRDX3 [51], or catalase [260], which are decreased in CF patients. To connect these modifications with CF specific features, a dysfunctional CFTR channel has been found to be associated with a reduced activity of Nrf-2 [261,262]. The presence of a defective CFTR appears to induce a pro-oxidative imbalance in epithelial cells and extracellular fluids of CF airways, which increase the levels of ROS. Constitutive defects on GSH reductase and NOX activities [263,264,265,266] together with intestinal malabsorption of fat-soluble antioxidant vitamins (vitamin E and carotenoids) [267,268] could promote a defective antioxidant protection and exacerbate oxidative stress indices, contributing to the progression of the clinical status in CF patients [269,270,271]. Moreover, ROS activate second messengers through phospholipases A2, C, and D, which induce cytokines and mucin production. Oxidative stress and inflammation can also affect surfactant biophysical activity, leading to early alterations of lung function in patients with CF [272]. Antibiotic treatment has been shown to prevent and control lung infections. These mainly consist of inhaled, nebulized or aerosolized forms of azithromycin, aztreonam and levofloxacin [273,274,275]. Alternatively, ciprofloxacin, cephalexin, amoxicillin, and doxycycline have also been recommended depending on the sensitivity patterns of the bacterial pathogens [276,277]. Colistin is also used [278]. To control airway inflammation, nonsteroidal anti-inflammatory drugs (NSAIDs) [279,280] and cromoglycate (cromolyn) [281] are used. To reduce the viscoelasticity of bronchial mucus secretions and promote its clearance from CF lungs, and to dilate the airways, bronchodilators such as inhaled β-agonists with humidified oxygen, a 3–6% hypertonic saline solution [282,283,284], and dornase alfa [285,286,287,288] are recommended. Furthermore, exercise [289] and chest physiotherapy including oscillating devices for mucus mobilization is being prescribed as well [290]. 5. Prospective Therapeutic Strategies 5.1. ALI/ARDS The scientific rationale for emerging therapies in ARDS is to pursue fundamental processes and mediators of its complex pathophysiology [291]. There are emerging therapies in Phase 3 trials assessing the potential benefits of corticosteroids such as dexamethasone [292,293] or budesonide/formoterol [294,295]. Moreover, supplementation with vitamin D [296] in a Phase 2 trial has shown a reduction in markers of vascular permeability from lung injury patients following esophagectomy in the post-operative period [297], although another trial using vitamin D to prevent acute respiratory tract infections has been less conclusive [298]. Other emerging therapies in Phase 2 trials include aspirin, which has attracted interest as a repurposed drug for ARDS [299,300], with some clinical studies [301] that show significant reduction in neutrophil infiltration into the alveolar space. Alternatively, different studies using mesenchymal stem cells (MSCs) and multipotent adult progenitor cells (MAPCs) have shown a biological decline in angiopoietin and a concomitantly reduced 28-day mortality, higher ventilator-free days, and higher ICU-free days [302]. Vitamin C acts as ROS scavenger, modulator of inflammatory mediators, and cofactor. In mouse models, ALI prevents the activation of NF-κB, and therefore attenuates the production of proinflammatory cytokines and boosts ion channel and pump expression, enhancing fluid clearance in the alveolar epithelium [303]. The phase 2 CITRIS-ALI trial is presently investigating the usefulness of vitamin C in sepsis-induced ALI [304] but no positive results have been reported as yet [305]. It was found that nebulized liquid heparin increased the number of ventilator-free days [306], and a Phase 2 trial to confirm the findings is awaited [307]. Anti-tissue factor antibodies such as ALT-836, which blocks binding to coagulation factor VIIa, have demonstrated attenuation of sepsis-induced ALI in animal models, and was successfully tested in a Phase 1 trial for ARDS [308]. A Phase 2 trial has been recently completed and disclosure of the results is pending [309]. Dilmapimod, a p38 MAPK inhibitor, has proven useful for reducing the severity of ALI in animal studies, although in human trials it has been unreliable [310,311]. Neutrophil elastase inhibitors such as sivelestat, have been shown to increase the ventilator-free days in ARDS patients with a high extravascular lung water content (>10 mL/kg) as compared with those with low pulmonary edema [312], although contradictory results have also been obtained [313,314]. Ulinastatin (or urinary trypsin inhibitor) is another physiological inhibitor of human neutrophil elastase with positive results in preclinical studies [315]. A meta-analysis of 29 Chinese randomized controlled trials (RCTs) indicated that ulinastatin was effective ameliorating ARDS [316]. Another multi-center Phase 2 RCT is ongoing to assess its safety and efficacy in ARDS [317]. Regarding granulocyte-macrophage colony stimulating factor (GM-CSF), preclinical models have demonstrated that it can limit alveolar epithelial cell injury and promote alveolar macrophage maturation. Nevertheless, a Phase 2 RCT enrolled only two-thirds of its intended number of participants and, although GM-CSF treatment appeared to be safe, it did not decrease ventilator free days or mortality of the ALI/ARDS patients [318]. Anti-CD14 antibodies protected against septic hypotension in animal models of pneumonia [319]. Two Phase 2 trials have been initiated in this regard, the former, in 2007, failed in recruiting people; and the latter is still recruiting [320]. Inhaled prostaglandins, such as epoprostenol and alprostadil, have been suggested to regionally dilate the pulmonary vasculature increasing arterial oxygenation in ARDS. However, a meta-analysis of 25 studies concluded that, although indeed inhaled prostaglandins improved oxygenation in ARDS, they did not improve pulmonary physiology or mortality [321]. Preclinical Studies The focus of preclinical studies has been basically on antioxidants, antiproteases, and signal transduction inhibitors. Histones have strong proinflammatory, cell damaging, and procoagulant activities in the airways. Targeting histones in the lung with neutralizing monoclonal antibodies (mAb) provides high-level protection against the development of ALI [322]. An alternative strategy for ALI-induced sepsis employed a non-anticoagulant heparin derivative that binds to histones and prevents histone-mediated cytotoxicity, mitigating mortality in sepsis mouse models [323]. Because of the variety of chemokines and cytokines, and the overlapping interactions with their receptors, in vivo blockade of these mediators with mAbs would likely not be effective in ALI patients. Nonetheless, the IL-1β receptor antagonist (anakinra), which neutralizes inflammasome-derived IL-1β and has proven effective in rheumatoid arthritis [324] and in complement-dependent collagen-induced arthritis in mice [325], might also improve ARDS outcomes. Among the antioxidants, there are several natural products such as curcumin, ginsenoside, alpinetine, and honokiol [326]. 5.2. Asthma Over the last few years, multiple biologics (typically mAbs) have been developed targeting various participants in allergies and asthma, but mainly directed toward the complex type 2 endotype [327,328]. In general, they are anti-inflammatory treatments [329]. The most prevalent biologics are omalizumab (anti-IgE) and mepolizumab (anti-IL-5). IL-5 has become a major target for both asthma and COPD due to the high proportion of patients with airway eosinophilia associated with disease severity [330]. Currently, three biologics, targeting IL-5 or its receptor, have been cleared by the Food and Drug Administration (FDA). Omalizumab was initially approved by the FDA in 2003 and binds to both the high-affinity and low-affinity IgE receptors, preventing free IgE from occupying the surface of mast cells and basophils [331]. It has several disadvantages, i.e., it must be administered by subcutaneous injection [332], it is expensive [333] and, moreover, an unusual form of anaphylaxis [334] and a possible higher rate of cardiac and cerebrovascular events can be ensued by this treatment. Anti-IL-5 (mepolizumab) was approved in late 2014 and receiving patients had decreased eosinophilic inflammation, reduced asthma exacerbations, improved asthma control markers, better quality of life [335,336], and reduced levels of some of the proteins that drive airway remodeling [337]. In another study on moderate persistent asthma, despite high-dose ICS, patients also showed decreased blood and sputum eosinophils but no change in FEV1, symptom scores, or need for rescue inhaler. After stopping anti-IL-5 treatment, eosinophils and asthma symptoms again increased [338]. Reslizumab, another mAb targeting IL- 5, approved in 2016 for patients with eosinophilic asthma, has proven beneficial on moderate-to-severe asthma symptoms, improving lung function and reducing exacerbations as compared with a placebo [339]. Reslizumab also decreased blood, sputum, and airway eosinophils and, more recently, reduced systemic corticosteroid dosing nearly 75% [340,341,342]. Benralizumab, a mAb targeting the IL-5Rα, was approved recently by the FDA [343] with positive results in asthma [344,345,346]. Finally, dupilumab, a mAb approved in 2017 that inhibits the IL- 4R subunit [347], has also shown encouraging results in asthma [348,349]. Regarding relevant future targets pending approval, lebrikizumab and tralokinumab, mAbs that target IL-13 [350,351], have not shown positive effects [352,353]. Tezepelumab (AMG157), a humanized mAb currently in Phase 3 [354] binds thymic stromal lymphopoietin, an epithelial cell-derived cytokine that drives allergic inflammatory responses [355]. Additionally, anti-IL-33 therapies are currently under development [356]. Conversely, non-Th2 inflammation targets are also being studied. IL-6 and IL-17 may promote both Th2 and non-Th2 inflammatory cascades. Brodalumab is a human mAb binding IL-17RA, which inhibits signaling of IL-17 and IL-25, with disappointing results in clinical trials [357]. Thus, this therapy has not been further pursued for asthma or COPD. C-X-C motif chemokine receptor 2 (CXCR2) antagonists such as navarixin (which decrease IL-8 levels) have reduced sputum and blood neutrophils, with no significant change in FEV1 [358], but has progressed to a Phase 2 trial [359]. An antisense oligonucleotide against C-C chemokine receptor 3 (CCR3) (co-administered with an antisense oligonucleotide that targets the c subunit of the IL-3, IL-5, and GM-CSF receptors), named TPI ASM8, has shown some efficacy in phase 2 trials [360]. Imatinib is a tyrosine kinases inhibitor that has shown promising results in a clinical study, reducing airway hyper-responsiveness as compared with a placebo [361]. Among drugs targeting TNF-α, etanercept stands out as a repositioning drug for asthma. A few studies employing etanercept have reported satisfactory results reducing bronchial hyperreactivity [362,363], whereas other studies have informed poor clinical efficacy in terms of lung function improvement and quality of life [364]. Others have shown a small but significant increase in the quality of life without changes on lung function [365]. Among anti-inflammatory treatments, antioxidant treatments stand out [98,366]. Vitamins (E, C, D, and A), carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin, and lycopene), and food supplements (selenium and zinc) seem to improve the prognosis of the disease [102,367,368]. Asthmatic adults with antioxidant-poor diets have lower forced expiratory volume in the first one second to the forced vital capacity (FEV1/FVC) ratio scores, increased plasma C-reactive protein, and were more likely to exacerbate than those on an antioxidant-rich diet [369]. Indeed, dietary antioxidant supplementation notably improved both symptoms and lung function in exercise induced asthma [370]. Preclinical Studies Thiol-based antioxidants are popular supplements to trigger GSH conversion. N-acetyl cysteine is the most commonly used thiol precursor. Thus, N-acetyl cysteine supplementation remarkably decreased inflammatory cytokines (IL-13, IL-5), neutrophil, and eosinophil numbers in the bronchoalveolar lavage fluid (BALF) from a mouse model [371], which has been associated with excessive bronchoconstriction [372]. Among natural extracts, sakuranetin is a flavonoid that can attenuate airway hyperresponsiveness, while decreasing oxidative stress (8-isoprostane), Th2 proinflammatory cytokines, IgE, and vascular endothelial growth factor levels in the lungs, similar to dexamethasone. Moreover, it can reverse airway remodeling by controlling NF-κB activation [373,374]. Astragalin, another flavonoid, suppresses eosinophil infiltration [375,376]. Resveratrol has been shown to decrease p47phox expression and ROS production, increase SOD levels, and reverse elevated TNF-α and inducible NOS (iNOS) from lung tissue [377,378]. Morin, an active ingredient obtained from Moraceae plants, abolished intracellular ROS and MAPK [86] and attenuated the extensive trafficking of inflammatory cells into BALF from ovalbumin (OVA)-challenged mice and rats [379]. Boerhavia procumbens inhibited oxidative stress pathways, reducing the anti-inflammatory response, and improving lung injury [380]. Esculentoside A and Sonchus asper extract significantly upregulated Nrf-2 expression, SOD activity, and intracellular GSH levels [381,382]. Oral treatment with Capsicum annuum L. methanolic extract remarkably decreased the pathophysiological signs of OVA-induced airway inflammation, reducing ROS levels of BALF in asthmatic mice [383]. Carissa opaca fruit extracts can restore the activities of antioxidant enzymes and lipid peroxidation [384,385]. Furthermore, antioxidant synthetics such as Y-27632, a Rho-kinase inhibitor, controls airway inflammation and responsiveness, the remodeling response, and oxidative stress in guinea pigs [386,387]. Treatment with 1400 W (an iNOS-specific inhibitor), nor-HOHA (an arginase inhibitor), or NaHS (a hydrogen sulfide (H2S) donor) decreased pro-contractile 8 isoprostane expression and modulated arginase 2 and iNOS pathways, contributing to reduced NF-κB expression in distal lung tissue. These inhibitors also mitigated eosinophil infiltration and increased tissue resistance and elastance [388,389]. HYDAMTIQ is a promising poly (ADP-ribose) polymerase inhibitor that prevents lung inflammation, airway remodeling and damage in asthma [390]. An angiotensin-I converting enzyme 2 (ACE2) activator, diminazene aceturate, attenuates allergic airway inflammation in a rat asthma model [391]. Diallyl sulfide decreases infiltrated inflammatory cell count and Th2 proinflammatory cytokines in BALF from OVA-challenged mice [392]. Mice treated with S-adenosylmethionine, a potent methyl donor, had decreased amounts of Th2 proinflammatory cytokines and 4-hydroxy-2-nonenal in lung tissues [393]. Pituitary adenylate cyclase-activating polypeptide reverses vanadate-induced airway hyperresponsiveness in rats, mainly through bronchodilator activity and counteraction of proinflammatory and pro-oxidative effects [394]. Furthermore, a multiple targeting approach against oxidizing molecules, PRRs and transcription factor modulators could improve outcomes in asthma. Flavonoids have stronger radical scavenging activity as compared with many other natural antioxidants because of multiple hydroxyl groups present in its chemical structure [395,396,397,398,399]. Ambroxol is a mucoactive agent with anti-inflammatory and antioxidant activities used to increase mucociliary clearance and regulate surfactant levels in the upper respiratory airways [400]. The salicylic acid derivative 5-aminosalicylic acid reduces leukocyte count, the expression of Th2 cytokines, and oxidative stress markers in the BALF from asthmatic mice [401]. Sitagliptin and Cinnarizine also reduce proinflammatory cytokine release and inflammatory infiltration, while restoring GSH and SOD, thus, playing a role attenuating airway inflammation and remodeling through antioxidative stress [402,403]. However, some of the above approaches have failed due to unanticipated side effects. Thus, as yet, no antioxidants have been employed as first-line therapy for asthma. 5.3. COPD Thus far, no anti-IL-5 therapies have been approved for use in COPD. However, two Phase 3 studies using mepolizumab showed improvements in exacerbation frequency from subjects who had an eosinophilic phenotype and a history of COPD exacerbations, despite triple therapy [404]. Nevertheless, other studies have indicated no positive effects [405]. Reslizumab has yet to be formally evaluated in clinical trials for COPD. Conversely, in a Phase 2 trial including COPD patients with eosinophilia, benralizumab treatment did not significantly reduce the annual rate of moderate or severe exacerbations [406,407]. However, significant improvements in FEV1 were observed in the overall study population, and the results of pre-specified subgroup analyses by baseline blood eosinophil count in individuals with benralizumab versus placebo have led to an ongoing Phase 3 trial to evaluate this biologic in COPD [408]. As in asthma, non-Th2 inflammation targets include CXCR2 and CCR3. Regarding corticosteroids, in contrast to asthma, glucocorticoid treatment of established COPD is rather ineffective in reducing chronic airway inflammation and progressive airway obstruction [409]. Current national and international guidelines endorse the use of inhaled long acting bronchodilators, ICSs, and their combination for maintenance treatment of moderate-to-severe stable COPD [410], although adverse effects may arise [411]. In fact, large clinical trials assessing the combination therapy (ICSs + LABAs) in a single inhaler for stable COPD patients have shown a good safety profile, a discreet but statistically significant reduction of severe exacerbations, and improvements of FEV1, quality of life, and respiratory symptoms in these patients [412,413]. Overexpression of histone deacetylase 2 restores glucocorticoid sensitivity in BAL macrophages from COPD patients [414]. Anti-cytokine and anti-chemokine treatments are being exploited in COPD but scarce trials using blocking antibodies against cytokines and chemokines or their receptors have proven successful [409]. Among those showing positive effects, the CXCR2 inhibitor MK-7123 (also known as SCH527123 or navarixin, already described in asthma) could reduce the chemotaxis of neutrophils [409]. MK-7123 treatment resulted in a significant reduction of sputum neutrophils and of sputum and plasma MMP9 and myeloperoxidase levels [415]. Numerous other drugs, including antibodies directed against specific inflammatory mediators such as cytokines (IL-18, IL-22, IL-23, IL-33, TSLP) and growth factors (GM-CSF) are under investigation for COPD. Preclinical Studies The treatment of respiratory symptoms is the focus of most therapies for COPD, since therapies for comorbidities are ineffective or inexistent. Thus, there is a need for the identification of the mechanisms which relate COPD to its comorbidities, and preclinical models have been developed to solve this [416]. Pharmacological activation of soluble guanylate cyclase, involved in the nitric oxide-cyclic guanosine 3′,5′-monophosphate (NO-cGMP) signaling pathway, has been shown to prevent the development of emphysema and pulmonary vascular remodeling in animal models of COPD [417]. Regarding the cardiovascular effects of COPD, N-acetyl cysteine or the proteasome inhibitor bortezomib attenuated muscle mass loss and wasting [418]. The inflammation is also very important and airway epithelial cells, oxidative damage, epithelial-mesenchymal transition, and airway remodeling have also been considered to be potential therapeutic targets [419]. The mesenchyme plays a key role in COPD, and bromodomain-containing protein (BRD) along with NF-κB, contribute to mesenchymal transition. Selective inhibitors of the epigenetic regulator BRD4, specifically targeting TLR3-induced airway inflammation, have been developed through structure-based drug design [420,421]. The aim is to decrease the levels of neutrophilic inflammation in the airways and prevent the alteration of the epithelial cell state, reducing myofibroblast growth in infection exposures. MSCs may also be used as a therapeutic strategy for the treatment of COPD, reducing inflammation, antimicrobial actions, and promoting lung epithelial and endothelial repair [422]. 5.4. Idiopathic Pulmonary Fibrosis (IPF) After several disappointing years of promising therapies that moved into clinical trials but failed to demonstrate efficacy in IPF [423], the anti-fibrotic drugs pirfenidone and nintedanib have been associated with significantly slower respiratory deterioration and perhaps prolonged survival [236,237,424], although with heterogenous responses and side effects. The understanding of the complex pathogenesis of IPF continues to increase [425,426]. Sustained alveolar epithelial cell injury and abnormal repair are increasingly recognized as the core mediators of the fibrotic process, with a relevant involvement of environmental triggers. The activation of multiple pathways related to maladaptive repair, involving fibroblast migration, proliferation, and extracellular matrix deposition has revealed a variety of prospective molecular targets of novel therapeutic agents currently being tested in early phase clinical trials. Pentraxin-2 (PTX-2) is a circulating protein that binds to monocytes, promoting epithelial healing and resolution of fibrosis. Thus, a recombinant human PTX-2 (serum amyloid P) analogue (PRM-151) has been shown to inhibit monocyte to fibrocyte differentiation and ameliorate fibrosis in a bleomycin-induced animal model of fibrosis [427,428]. A Phase 1 trial showed a non-significant but improving effect of PRM-151 on FVC and six-min walking distance (6MWD) during the treatment [429]. Further Phase 2 studies have demonstrated a significant reduction in pulmonary function deterioration and stability in 6MWD over 24 weeks as compared with a placebo, although with relevant adverse events [430,431]. The launch of a Phase 3 trial for PRM-151 in IPF has been announced, using FVC as a primary end point and 6MWD as a key secondary end point. Among the anti-connective tissue growth factor antibodies, the antagonist pamrevlumab (FG-3019) in the PRAISE study [432] was established to have a significant effect preventing lung function decline of 160 IPF patients, yet full peer-reviewed data are still awaited [433]. The re-initiation of Phase 3 trials has just been announced. PBI-4050 is a synthetic analogue of a medium-chain fatty acid acting through G protein-coupled receptors and showing anti-fibrotic activities such as inhibition of epithelial–mesenchymal transition and fibrocyte/fibroblast recruitment, migration, proliferation and differentiation, among others [434]. A Phase 2 trial has shown no safety concerns [435]. While there was slowing or stability in FVC, a statistically significant decrease was observed only combining PBI-4050 and pirfenidone but not PBI-4050 and nintedanib, implying a possible drug–drug interaction. Additional studies of PBI-4050, either alone or in combination with nintedanib, are currently being considered. In a Phase 2a study [436], GLPG1690, an oral selective inhibitor of autotaxin (an enzyme increased in IPF and involved in cell apoptosis and endothelial cell damage) was analyzed and was well tolerated by IPF patients, with a good safety profile. Moreover, as secondary end points, preliminary efficacy analyses demonstrated target engagement and encouraging results towards halting FVC decline [437]. International Phase 3 trials to assess the efficacy of GLPG1690 in IPF are ongoing [438]. Leukotrienes are also increased in IPF [439,440]. Thus, additional ongoing trials include leukotriene antagonists such as tipelukast, currently explored in a Phase 2 trial [441]. Among protein kinase inhibitors, a recent Phase 1 study showed proper safety and tolerability of a selective protein kinase inhibitor of the Rho-associated coiled-coil containing protein kinase 2 (ROCK2). The trial is currently in Phase 2 [442,443]. Moreover, a current Phase 2 [444] trial is evaluating CC-90001, a second-generation Jun N-terminal kinase (JNK) inhibitor after a first-generation JNK inhibitor (CC-930) showed a dose-dependent trend of reduction in MMP7 and surfactant protein D (SP-D) biomarker plasma levels [445]. Regarding anti-integrin antibodies, a partial inhibition of integrin αvβ6 in rodents blocked the development of pulmonary fibrosis processes without aggravating the inflammatory response [446]. The safety and tolerability of a humanized monoclonal antibody (BG00011) against this integrin has been analyzed in a Phase 2 trial [447]. The study has been completed recently, although its outcome is still pending. Phosphatidylinositol 3-kinase/Protein kinase B (PI3K/Akt) pathway inhibitors may be associated with halting fibrosing processes [448], as suggested in a Phase 1 trial [449,450] and evidenced in another recent study using omipalisib [451]. Sirolimus is currently under examination in a Phase 2 trial [452]. The B lymphocyte antigen CD20 is targeted by rituximab, which is currently being assessed in an IPF Phase 2 study [453]. Furthermore, a Phase 2 trial examined combined plasma exchange, rituximab, and steroids [454]. While peer-reviewed results are pending, a pilot trial stated good outcomes regarding autoantibody reduction for acute IPF exacerbations [455]. A Phase 3 trial testing the antibiotic combination co-trimoxazole (trimethoprim and sulfamethoxazole) is currently operating [456]. Finally, other anti-inflammatory drugs are likewise in clinical research for IPF, i.e., lebrikizumab [457], tralokinumab [458], and azithromycin [459]. Preclinical Studies Administration of the senolytic drug quercetin attenuates the proinflammatory phenotype of bleomycin-induced senescence in fibroblasts [460]. Moreover, the anti-fibrotic activity of quercetin was superior to that of vitamin E in bleomycin-induced pulmonary fibrosis in rats [461]. When given in combination, the tyrosine kinase inhibitor dasatinib and quercetin depleted senescent cells and improved lung function and fibrotic markers following bleomycin injury [462,463,464,465]. Different preclinical and clinical trials testing the senolytic cocktail dasatinib plus quercetin has shown both positive outcomes [466] and negative ones [467,468]. Other senolytics with positive preclinical studies are curcumin, fisetin and fisetin-loaded mesoporous carbon nanoparticles [469], and navitoclax [470]. Therefore, the promising expectations generated in preclinical studies supports proof-of-principle clinical trials with senolytic agents for IPF treatment [471]. Conversely, it has also been suggested that senolytic drugs could be detrimental to IPF patients [460]. 5.5. Cystic Fibrosis (CF) To address the most prevalent causal defects in the CFTR Cl– channel leading to CF, two biomolecular modulators are needed, i.e., CFTR correctors, to increase the amount of properly folded mutant CFTR protein at the plasma membrane, and CFTR potentiators, to allow effective gating (channel opening and closing) of the abnormal CFTR [472,473,474]. Nevertheless, a more thorough division might also include stabilizers, read-through agents, and amplifiers [475]. Either alone or combined, these modulators tend to restore transepithelial Cl− transport to CF airway epithelia expressing CFTR mutations such as the most prevalent F508del, improving hydration and restoring mucociliary clearance [476,477]. Four drugs have been recently approved by the FDA for that purpose [474], the potentiator Ivacaftor (VX-770) for individuals with CF holding a G551D CFTR mutation, and the following three correctors: Lumacaftor (VX-809), developed to increase the amount of F508del CFTR that reaches the cell surface [478,479], Tezacaftor (VX-661), and Elexacaftor (VX-445). Furthermore, their combinations are also being assayed, i.e., Orkambi (lumacaftor/ivacaftor) for patients homozygous for F508del CFTR [480], Symdeko (tezacaftor/ivacaftor), and Trikafta (elexacaftor/tezacaftor/ivacaftor). Most recently, there has been an explosion of novel modulators [481] and others are under investigation including ELX-02, Posenacaftor (PTI-801), Galicaftor (ABBV-2222), ABBV-3221, FDL169, Deutivacaftor (VX-561), ABBC-974 (GLPG-1837), and Nesolicaftor (PTI-428) [482,483,484,485,486,487,488,489,490,491], among others. Despite a thorough knowledge of the undergoing inflammatory process in CF, there are relatively few anti-inflammatory drugs in clinical use [492]. Corticosteroids were shown to confer some benefit but their long-term use is associated with unacceptable side effects [493,494,495]. The non-steroidal anti-inflammatory agent ibuprofen has also demonstrated benefits [279,280]. Particularly in younger patients, it has been associated with an increased survival rate [496,497], but it requires a strict dose control and has associated renal and gastrointestinal side effects [279]. A large Phase 2 RCT of the leukotriene B4 (LTB4) receptor antagonist, BIIL 284 BS (amelubant), surprisingly demonstrated an excess of pulmonary exacerbations as compared with a placebo [498]. Conversely, CTX-4430 decreases the production of LTB4, an inflammatory mediator elevated in CF [499] and is presently undergoing a Phase 2 trial [500]. Andecaliximab, an antibody against MMP9, is undergoing a Phase 2b trial [501] but the baseline FEV1 required for this drug limits its use in very severe CF and this trial has been discontinued. Another compound in Phase 1 is POL6014, a synthetic neutrophil elastase blocker [502]. Other anti-inflammatory compounds under clinical development are α-1 anti-trypsin [503], the elastase inhibitor AZD9668 [504], and JBT-101 (ajulemic acid, or Lenabasum), an oral selective cannabinoid receptor type 2 (CB2) agonist that decreases neutrophilic inflammation inhibiting LTB4 and promotes resolution of inflammation through modulation of arachidonic acid metabolism [505]. A Phase 2, double-blind, placebo-controlled study, in adult CF patients, demonstrated decreased levels of several sputum inflammatory markers and reduced exacerbations in response to JBT-101, with no serious adverse effects reported [506,507]. A Phase 2b study is underway. Indeed, CB2 activation has shown anti-inflammatory effects including stimulating lipoxin A4 (LXA4) synthesis, decreasing proinflammatory cytokine secretion, and neutrophil trafficking to the lung [508,509]. Anti-proteases have been under investigation in CF since 1990. For example, the already described α1-antitrypsin suppressed inflammatory markers including free neutrophil elastase, proinflammatory cytokines, and neutrophils [510,511]. Other neutrophil elastase inhibitors include recombinant secretory leukocyte protease inhibitor (rSLPI) and the small-molecule drug EPI-hNE4 (depelstat) [512]. Among other inflammatory therapies, hydroxychloroquine, a dihydrofolate reductase inhibitor that increases intracellular pH, was negatively evaluated in a small 28-day study in CF [513]. A CF clinical trial regarding SB-656933, a CXCR2 antagonist, concluded that this molecule might modulate airway inflammation [514]. Conversely to refractory asthma, few CF studies have considered the use of chemotherapeutics. Low dose of the immunosuppressant cyclosporin A diminished the need for systemic corticosteroids in one small case series. In a pilot study, methotrexate increased FEV1 and decreased total serum immunoglobulins in five CF patients after one year of treatment [515], showing tolerable adverse effects. IL-8 decoys are used as an anti-inflammatory anti-neutrophil elastase strategy [516,517]. Other novel anti-inflammatory compounds under review include the already mentioned lipoxins and resolvins. Arachidonic acid-derived lipoxins such as LXA4 attenuate neutrophil chemotaxis, respiratory burst, IL-8 production, and accelerate apoptosis [518,519,520]. Because of low LXA4 levels in CF airways, stable LXA4 agonists have been developed as prospective therapeutics. Decosahexanoic acid- and omega-3 eicosapentanoic acid-derived resolvins D1 and E1 also mitigate inflammation, preventing chemotaxis and promoting clearance of apoptotic neutrophils [521,522,523,524]. Analogously to LXA4, resolvins stimulate a cytoprotective effect on airway epithelial cells [525,526]. Retinoids foster extracellular matrix homeostasis. Recent Phase 1b studies involving LAU-7b, an oral solid-dosage form of the retinoid fenretinide, showed safety and tolerability in adult CF patients, encouraging progression to Phase 2 trials [527]. Antioxidant therapies have not been yet settled in clinical practice [528]. In fact, despite the commercial development of many natural antioxidants as dietary supplements, there is no sound clinical trial evidence of their effectiveness in any clinical condition [529] with the exception of GSH (administered either orally or by inhalation) [530,531,532] with some drawbacks [533]. Though not quite clear [534], high doses of β-carotene appear to improve lung function and decrease oxidative stress in some cases [535]. The application of deferiprone (L1) as an iron chelating drug/pharmaceutical antioxidant is under way. Its use is being considered as a main, alternative, or adjuvant therapy in many diseases involving oxidative damage [536,537]. N-acetyl cysteine, initially developed as a mucolytic, is being repurposed as an antioxidant [538], inhibiting H2O2 and increasing GSH [531]. Of significance is the malabsorption of fat-soluble antioxidants in CF patients such as tocopherols, carotenoids, and coenzyme Q10 (Co-Q10), and that of essential fatty acids. Vitamin E might become a good supplementation to overcome this deficiency [539,540,541,542,543], along with carotenoids [544] and ascorbic acid (vitamin C) as nutritional supplements. Multivitamin supplements with high bioavailability containing Co-Q10 would also be a good alternative [545,546]. One recent study regarding multivitamin supplements showed a decrease in circulating inflammatory markers and a decrease in pulmonary exacerbations [547]. Alternatively, several hydro soluble antioxidants, oligoelements, and enzymatic antioxidants such as Vitamin C, selenium and selenium-dependent peroxidases [548,549,550], zinc, and copper [551] have yielded promising results awaiting further clinical trials. A randomized double-blind placebo-controlled trial has examined the outcome of short-term melatonin administration (3 mg for three weeks) on sleep and oxidative stress markers in CF [552]. Accordingly, with the expected activity synchronizing the sleep-wake cycle and its antioxidant properties, treatment with this hormonal substance reduced nitrite levels in exhaled breath condensate and improved sleep indices. Preclinical Studies Anti-inflammatory cytokines and antibodies to proinflammatory cytokines may show efficacy in CF. IL-10 possesses anti-inflammatory properties. Interferon-γ1b, another cytokine with immunomodulatory activities, did not improve pulmonary function nor alter bacterial burden or inflammatory markers in the sputum in a multicenter clinical trial, despite its ability to restore macrophage activation and antimicrobial, antiproliferative, and anti-fibrotic functions in CF cell models [553]. To inhibit specific proinflammatory mediators, antibodies to intercellular adhesion molecule 1 (ICAM-1) and IL-8 have been evaluated in preclinical studies [554], although they never progressed to clinical trials. Anti-IL-17 antibodies reduced airway neutrophilia in mice exposed to LPS [555]. Because of the similarities between CF airway inflammation and hyperinflammatory conditions such as rheumatoid arthritis or psoriasis, for which clinical trials using anti-IL-17 antibodies have been completed, targeting IL-17 could also be of therapeutic value for CF treatment. Among intracellular signaling modulators, ibuprofen (previously described), and IL-10 inhibit NF-κB activation. NF-κB activity inhibition also occurs through upregulation of peroxisome proliferator activating receptor (PPAR-γ) using PPAR-γ agonists such as thiazolidinediones (glitazones) [556,557,558]. Troglitazone and ciglitazone activate PPAR-γ in primary CF airway epithelial cells and reduce the production of proinflammatory mediators in response to P. aeruginosa [559]. Statins have anti-inflammatory effects, including the ability to inhibit neutrophil migration, decrease proinflammatory cytokine production, and increase transcriptional activation of PPAR [560,561,562]. Agents that augment endogenous NO production, exhibiting anti-inflammatory activity, have also been examined. In a rodent model of chronic airway infection, L-arginine, which increases NO production, was associated with reduced tissue damage, decreased neutrophil recruitment, and reduced IL-1β [563]. Synthetic triterpenoids are small-molecule derivatives of naturally occurring compounds holding cytoprotective functions that increase antioxidant Nrf2 activity, and therefore could also be considered for clinical trials. In addition, consumption of long chain fatty acids (omega-3 supplements) seems not to have a clear anti-inflammatory effect and, consequently, a positive benefit on CF disease severity [564]. Among emerging antioxidant and anti-inflammatory approaches for CF, targeting NF-κB with natural compounds such as resveratrol and plant extracts is highlighted. Resveratrol (3,5,4′ trihydroxystilbene, “E” form) is one of the most investigated natural antioxidants with a purported activity as NF-κB inhibitor. The antioxidant activity of resveratrol has been reported in several studies and also occurs in lung tissues, suggesting that resveratrol has potential as a therapeutic agent in respiratory diseases [260,565,566]. The drug Meveol® is a complex of lactoferrin and the anion hypothiocyanite (OSCN−), with a proposed in vivo antimicrobial activity [567] to be evaluated in clinical trials as aerosol treatment for lung infections in CF patients. A role for this drug in the control of H2O2 levels in the airway surface liquid remains to be investigated. In addition, preclinical studies [568] have shown novel anti-inflammatory effects and antimicrobial potential of the anion thiocyanate (SCN−) in lung infection, which decreases BALF chemokine keratinocyte chemoattractant (KC) (analog to human IL-8), IL-1β, TNF-α, and airway neutrophil infiltrate concurrent with the infectious stimulus, and enhances bacterial clearance in both wild-type and transgenic mice overexpressing the β subunit of the epithelial sodium channel Scnn1 (βENaC). Therapeutic potential of selenium-derived compounds may derive from their significant activity as inducers of phase II enzymes such as quinone reductase and GSH-S-transferase [569], increasing the capacity to metabolize/detoxify endobiotics generated during oxidative stress and inflammation [570]. 6. Concluding Remarks Because inhaled oxygen along with environmental pollutants, pathogens, and allergens, which have intrinsic oxidative potential, dissolve in the respiratory epithelial lining fluid, oxidative stress and inflammation take center stage in the wide spectrum of respiratory pathologies, a major source of disability and death following cardiovascular diseases. Thus, a timely diagnosis, treatment, as well as the management of pulmonary diseases is important. In that sense, preventive measures such as enhancement of antioxidant defenses or corrective actions to mitigate abnormal immune-inflammatory responses, whether efficacious, could provide more options for patients and clinicians. Nevertheless, the last two decades have witnessed no major breakthroughs regarding medications for most of the respiratory diseases (Table 1). On the one hand, traditional adjuvant therapies such as mechanical lung ventilation for ALI/ARDS or chest physiotherapy and antibiotic therapy in CF improve patient survival slightly. On the other hand, the use of corticosteroids has become commonplace as anti-inflammatory treatment, although with limited efficacy and relevant side effects. Thus, novel drugs or drug combinations targeting relevant players in the disease process, such as neutrophil elastase inhibitors for ALI/ARDS and CF, antibodies against cytokines, chemokines or its receptors for asthma, COPD and CF, anti-fibrotic drugs for IPF, and, ultimately, the recently approved CF therapies targeting CFTR mutations (Figure 2) might represent a step forward to increase specificity and reduce adverse events. Moreover, new cutting-edge technologies, including single-cell next-generation sequencing, genome-wide in silico or phenotypic screenings to identify novel drug targets, and stem cell therapeutics should yield more efficacious and safe drugs to approach personalized treatments for a variety of airway dysfunctions. In fact, by gaining a better understanding of lung pathophysiology at the molecular level using new emerging technologies, the achievement of better outcomes in patients with respiratory pathologies will become a reality. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author Contributions J.C. wrote and edited the manuscript; J.M.A. wrote and supervised the manuscript. Both authors have read and agree to the published version of the manuscript. Funding J.C. is supported by a grant from the “Associació Catalana de Fibrosi Quística”. J.M.A. has received support from the Ministerio de Economía y Competitividad (Madrid, Spain) (grants FIS-ISCIII PI13/01490 and PI16/00377, co-funded by FEDER funds/European Regional Development Fund (ERDF)-a way to build Europe-), and from the Generalitat de Catalunya (grant 2017SGR 00291). J.M.A. is sponsored by the “Researchers Consolidation Program” from the SNS-Dpt. Salut Generalitat de Catalunya (Exp. CES06/012). Conflicts of Interest The authors report no conflict of interest in this work. Figure 1 Redox imbalance in the conductive airways of patients affected by cystic fibrosis (CF). Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in lungs prevents Cl− secretion and induces Na+ hyperabsorption at the airway apical surface, dehydration and impairment of mucociliary clearance. These events favor bacterial infection and prevent its elimination, inducing epithelial cells to secrete proinflammatory cytokines such as IL-8 and IL-6 and TNF-alpha, which attract neutrophils at the site of infection. As a result, a vicious cycle of neutrophilic inflammation and oxidative stress, produced by the release of large amounts of reactive oxygen species (ROS) both from epithelial cells and neutrophils through DUOX and NOX2, respectively, leads to irreversible airway destruction and fibrosis. Furthermore, low glutathione (GSH) levels further increase the oxidative stress. ROS also increase the migration of neutrophils from capillary venules. Figure 2 Different CFTR modulators and their targets. Abnormal CFTR protein biosynthesis/function according to the following different classes of CFTR gene mutations: Class I mutants involve no protein synthesis. Premature stop codons, frameshifts, or deletions preclude translation of full-length CFTR; Class II mutants, among them the most common mutation, F508del, have impaired trafficking due to incorrect folding; Class III mutants have defective channel gating; Class IV mutants hold reduced function, such as reduced chloride (Cl−) conductance; Class V mutants allow a reduced CFTR cannel number or maturation as a result of amino acid substitution or alternative splicing; and Class VI mutants support a less stable protein, since the recycling CFTR channel is sent for lysosome degradation. These phenotypes can be corrected by rationally designed drugs or drug combinations termed correctors (C1, targeted to class I and class V mutations and C2, targeted to class II mutations), and potentiators (P, targeted to class III–VI mutations). ijms-21-09317-t001_Table 1Table 1 Most relevant drugs according to respiratory disease type. Disease Drug Target Biologic Function Trial Reference ALI/ARDS Corticosteroids (dexamethasone, budesonide and formoterol) Corticosteroid receptors Reduce the signs and symptoms of inflammatory conditions Phase 3 [292,293,294,295] ALI/ARDS Aspirin Cox-1 and Cox-2 Significant reduction in neutrophil infiltration into the alveolar space Phase 2 [299,300,301] ALI/ARDS MSCs and MPAs - Reduction in angiopoietin decreased 28-day mortality, higher ventilator-free days and higher ICU-free days Phase 2 [302] ALI/ARDS ALT-836 Tissue factor (TF) or TF-factor VIIa Blocks binding to coagulation factor VIIa and attenuation of sepsis-induced ALI Phase 2 [308,309] ALI/ARDS Dilmapimod p38 MAPK Inhibitor Reduces severity of ALI Phase 2 [310,311] ALI/ARDS Ulinastin Physiological human inhibitor of neutrophil elastase Effective in ameliorating ARDS Phase 2 [315,316,317] ALI/ARDS Anti-CD14 antibodies Amti-CD-14 Antibodies which protect against septic hypotension Phase 2 [319,320] Asthma and COPD Omalizumab Anti-IgE Binds to free human IgE, forming small-size immune complexes, blocking its interaction with the high-affinity IgE receptor and preventing its contact with mast cells and basophils Approved [331,332,333,334] Asthma and COPD Mepolizumab Anti-IL-5 Decreases eosinophils in blood and sputum; fewer asthma exacerbations, better asthma control, improved quality of life, and reduced proteins involved in airway remodeling Approved for asthma; Phase 2 for COPD Asthma: [335,336,337,338]/COPD: [404,405] Asthma and COPD Reslizumab Anti-IL-5R Decreases blood, sputum, and airway eosinophils, reduces asthma exacerbations, improves lung function, and reduces systemic corticosteroid dosing by as much as 75% Approved [339,340] Asthma and COPD Benralizumab Anti-IL-5 Positive results in asthma. Decrease airway eosinophilia Approved Asthma: [343,344,345,346]/COPD: [406,407,408] Asthma Depilumab Anti-IL-4R Positive results in asthma. Decrease airway eosinophilia Approved [347,348,349] Asthma and COPD Tezepelumab Humanized monoclonal antibody Binds thymic stromal lymphopoietin, an epithelial-cell–derived cytokine that drives allergic inflammatory responses Phase 3 [354,355] Asthma and COPD Navarixin CXCR2 antagonist Reduces sputum and blood neutrophils; no significant change in FEV1 Phase 2 Asthma: [358,359]/COPD: [409] Asthma Etanercept TNF-α Reduces bronchial hyperreactivity; small but significant increase in quality of life Clinical [362,363,364,365] COPD ICS + LABA Corticosteroid receptors + β-adrenergic receptors Significant reduction in the number of severe exacerbations and improvement in FEV1, quality of life, and respiratory symptoms in stable COPD patients Approved [412,413] IPF Pirfenidone and nintedanib TGF-β and angiokinase Significant reduction of respiratory deterioration in IPF and, perhaps, prolonged survival Phase 3 [236,237,424] IPF PRM-151 Protein that binds to monocytes promoting epithelial healing and resolution of fibrosis Ameliorates fibrosis in a bleomycin- and TGF-β-overexpressing animal model of fibrosis Phase 2, heading for phase 3 [427,429,430,431] IPF Pamrevlumab CTGF Reduction of lung function decline Phase 2, heading for Phase 3 [433] IPF PBI4050 Analogue of a medium-chain fatty acid. Activates the GPR40 receptor, while it suppresses GPR84 activity, Inhibition of endoplasmic reticulum stress and ROS production, epithelial–mesenchymal transition and fibrocyte/fibroblast recruitment, migration, proliferation, and differentiation Phase 2 [434,435] IPF GLPG1690 Autotaxin Selective autotaxin inhibitor. Enzyme increased in IPF and involved in cell apoptosis and endothelial cell damage, and LPA inhibitor Phase 3 [436,437,438] IPF Tipelukast Leukotriene antagonists Downregulation of genes that promote fibrosis, such as LOXL2, collagen type 1, and TIMP-1; and genes responsible for promoting inflammation like CCR2 and MCP-1. Phase 2 [441] IPF KD025 Selective ROCK2 inhibitor Downregulates the ability of T cells to secrete IL-21 and IL-17 in response to T-cell receptor stimulation in vitro; restores disrupted immune homeostasis Phase 2 [442,443] IPF CC-90001 Second-generation JNK inhibitor Reduces the development of fibrosis, as evidenced by a 48% reduction in collagen and a 53% reduction in α-smooth muscle actin Phase 2 [444] IPF BG00011 Humanized monoclonal antibody targeting the alpha-v beta-6 (αvβ6) integrin receptor TGF-β suppression as evidenced by reduction in pSMAD2 signaling and TGF-β dependent gene expression in bronchoalveolar lavage (BAL) cells; preclinical models have shown maximal fibrosis inhibition correlating with 70% pSMAD reduction. Phase 2 [447] IPF Omipalisib PI3K/Akt pathway inhibitor Halts fibrosing processes Phase 1 [451] IPF Sirolimus mTOR Reduces the number of circulating fibrocytes Phase 2 [452] IPF Rituximab CD20 surface molecule of B lymphocytes Reduction of autoantibodies, a favorable safety profile and, possibly, stabilization of lung function. Phase 2 [453,454,455] IPF Cotrimoxazole Antibiotic Antibacterial drug Phase 3 [456] CF Lumacaftor CFTR corrector C1 Increases the amount of F508del-CFTR that reaches the cell surface Approved [478,479] CF Ivacaftor CFTR potentiator CF patients possessing a G551D CFTR mutation Approved [571] CF Orkambi CFTR corrector (C1) For patients homozygous for F508del-CFTR; increases the amount of F508del-CFTR that reaches the cell surface Approved [480] CF Ibuprofen Cox-1 and Cox-2 Slows the progression of lung disease in children with CF Approved [279,280,496,497] CF Amelubant LTB4 receptor antagonist Eicosanoid modulator; anti-inflammatory activity Phase 2 [498] CF POL6014 Neutrophil elastase function blocker Clear inhibition of neutrophil elastase in the sputum of subjects with CF after single dosing Phase 1 [502] CF CTX-4430 Leukotriene A4 hydrolase (LTA4H) inhibitor. Decreases the production of LTB4 LTA4H and LTB4 are strongly associated with the development of many conditions involving inflammation, including CF Phase 2 [499,500] CF JBT-101 Selective CB2 agonist. Decreases neutrophilic inflammation by inhibiting LTB4 and promotes resolution of inflammation by modulation of arachidonic acid metabolism Reduction in some sputum inflammatory markers; reduction of exacerbations in response to lenabasum, with no serious adverse effects reported Phase 2 heading for Phase 2b [505,507] CF Thiazolidinediones (glitazones) Inhibition of NF-κB activity through upregulation of peroxisome proliferator activating receptor (PPAR) Reduce systemic inflammation in polymicrobial sepsis by modulation of signal transduction pathways Approved [556,557,558] CF Troglitazone and ciglitazone PPAR activators Reduce production of proinflammatory mediators in response to P. aeruginosa Approved [559] CF α1-antitrypsin Serine protease inhibitor Suppresses inflammatory markers, including free neutrophil elastase, proinflammatory cytokines and neutrophils Phase 2 [503] CF SB-656933 CXCR2 antagonist Promising modulator of airway inflammation Phase 2 [514] CF LAU-7B Retinoids Promotes extracellular matrix homeostasis; safe and well tolerated. Phase 1b [527] CF Lenabasum Cannabinoid receptor type 2 (CB2) CB2 is found primarily on the surfaces of activated immune cells; upon binding to the CB2 receptors, lenabasum triggers the production of proinflammatory mediators, reducing inflammation; reduces the number of inflammatory cells and inflammatory mediators found in the sputum; FEV1 was stable throughout the study for both lenabasum and placebo groups. Phase 2, heading for 2b [506] CF GSH Endogenous antioxidant Improves lung function and decreases oxidative stress Phase 2 [530,531,532,533] CF β-carotene Natural antioxidant Improves lung function and decreases oxidative stress Phase 1 [534,535] CF Deferiprone (L1) Chelating drug/pharmaceutical antioxidant Used as a main, alternative or adjuvant therapy in many pathological conditions - [536,537] CF N-acetyl cysteine Antioxidant Inhibits H2O2 and increases GSH Phase 2b [531,538] ==== Refs References 1. Moldoveanu B. Otmishi P. Jani P. Walker J. Sarmiento X. Guardiola J. Saad M. Yu J. Inflammatory mechanisms in the lung J. Inflamm. Res. 2009 2 1 11 22096348 2. García-Bellmunt L. Sibilia O. Mecanismos de defensa pulmonar Med. Respir. 2013 6 15 24 3. LeMessurier K.S. Tiwary M. Morin N.P. Samarasinghe A.E. Respiratory Barrier as a Safeguard and Regulator of Defense Against Influenza A Virus and Streptococcus pneumoniae Front. Immunol. 2020 11 3 10.3389/fimmu.2020.00003 32117216 4. Ganesan S. Comstock A.T. Sajjan U.S. Barrier function of airway tract epithelium Tissue Barriers 2013 1 e24997 10.4161/tisb.24997 24665407 5. Yuksel H. Turkeli A. Airway epithelial barrier dysfunction in the pathogenesis and prognosis of respiratory tract diseases in childhood and adulthood Tissue Barriers 2017 5 e1367458 10.1080/21688370.2017.1367458 28886270 6. Andrani F. Aiello M. Bertorelli G. Crisafulli E. Chetta A. Cough, a vital reflex. Mechanisms, determinants and measurements Acta Biomed. 2018 89 477 480 7. Nawroth J.C. Van Der Does A.M. Ryan A. Kanso E. Multiscale mechanics of mucociliary clearance in the lung Philos. Trans. R. Soc. B Biol. Sci. 2020 375 20190160 10.1098/rstb.2019.0160 8. Twigg H.L. Humoral immune defense (antibodies): Recent advances Proc. Am. Thorac. Soc. 2005 2 417 421 10.1513/pats.200508-089JS 16322592 9. Sheehan G. Garvey A. Croke M. Kavanagh K. Innate humoral immune defences in mammals and insects: The same, with differences? Virulence 2018 9 1625 1639 10.1080/21505594.2018.1526531 30257608 10. Hartl D. Tirouvanziam R. Laval J. Greene C.M. Habiel D. Sharma L. Yildirim A.Ö. Dela Cruz C.S. Hogaboam C.M. Innate Immunity of the Lung: From Basic Mechanisms to Translational Medicine J. Innate Immun. 2018 10 487 501 10.1159/000487057 29439264 11. Hiemstra P.S. McCray P.B. Bals R. The innate immune function of airway epithelial cells in inflammatory lung disease Eur. Respir. J. 2015 45 1150 1162 10.1183/09031936.00141514 25700381 12. Aulakh G.K. Neutrophils in the lung: “The first responders” Cell Tissue Res. 2018 371 577 588 10.1007/s00441-017-2748-z 29250746 13. Ramirez G.A. Yacoub M.-R. Ripa M. Mannina D. Cariddi A. Saporiti N. Ciceri F. Castagna A. Colombo G. Dagna L. Eosinophils from Physiology to Disease: A Comprehensive Review BioMed Res. Int. 2018 2018 9095275 10.1155/2018/9095275 29619379 14. Chiu S. Bharat A. Role of monocytes and macrophages in regulating immune response following lung transplantation Curr. Opin. Organ Transplant. 2016 21 239 245 10.1097/MOT.0000000000000313 26977996 15. Byrne A.J. Mathie S.A. Gregory L.G. Lloyd C.M. Pulmonary macrophages: Key players in the innate defence of the airways Thorax 2015 70 1189 1196 10.1136/thoraxjnl-2015-207020 26286722 16. Cong J. Wei H. Natural killer cells in the lungs Front. Immunol. 2019 10 1416 10.3389/fimmu.2019.01416 31293580 17. Erjefält J.S. Mast cells in human airways: The culprit? Eur. Respir. Rev. 2014 23 299 307 10.1183/09059180.00005014 25176966 18. Peters M. Peters K. Bufe A. Regulation of lung immunity by dendritic cells: Implications for asthma, chronic obstructive pulmonary disease and infectious disease Innate Immun. 2019 25 326 336 10.1177/1753425918821732 31291810 19. Kim H.J. Kim C.H. Kim M.J. Ryu J.H. Seong S.Y. Kim S. Lim S.J. Holtzman M.J. Yoon J.H. The induction of pattern-recognition receptor expression against influenza a virus through Duox2-derived reactive oxygen species in nasal mucosa Am. J. Respir. Cell Mol. Biol. 2015 53 525 535 10.1165/rcmb.2014-0334OC 25751630 20. Tengroth L. Millrud C.R. Kvarnhammar A.M. Georén S.K. Latif L. Cardell L.O. Functional effects of Toll-Like Receptor (TLR)3, 7, 9, RIG-I and MDA-5 stimulation in nasal epithelial cells PLoS ONE 2014 9 e98239 10.1371/journal.pone.0098239 24886842 21. El-Zayat S.R. Sibaii H. Mannaa F.A. Toll-like receptors activation, signaling, and targeting: An overview Bull. Natl. Res. Cent. 2019 43 1 12 10.1186/s42269-019-0227-2 22. Reynolds J.M. Dong C. Toll-like receptor regulation of effector T lymphocyte function Trends Immunol. 2013 34 511 519 10.1016/j.it.2013.06.003 23886621 23. Taher T.E. Bystrom J. Ong V.H. Isenberg D.A. Renaudineau Y. Abraham D.J. Mageed R.A. Intracellular B Lymphocyte Signalling and the Regulation of Humoral Immunity and Autoimmunity Clin. Rev. Allergy Immunol. 2017 53 237 264 10.1007/s12016-017-8609-4 28456914 24. Gomes E.C. Florida-James G. Lung Inflammation, Oxidative Stress and Air Pollution Lung Inflammation IntechOpen London, UK 2014 25. Lodovici M. Bigagli E. Oxidative Stress and Air Pollution Exposure J. Toxicol. 2011 2011 487074 10.1155/2011/487074 21860622 26. Ozcan A. Ogun M. Biochemistry of Reactive Oxygen and Nitrogen Species Basic Principles and Clinical Significance of Oxidative Stress IntechOpen London, UK 2015 27. Dröse S. Brandt U. Molecular mechanisms of superoxide production by the mitochondrial respiratory chain Adv. Exp. Med. Biol. 2012 748 145 169 22729857 28. Lenaz G. Mitochondria and reactive oxygen species. Which role in physiology and pathology? Adv. Exp. Med. Biol. 2012 942 93 136 22399420 29. Del Río L.A. López-Huertas E. ROS generation in peroxisomes and its role in cell signaling Plant Cell Physiol. 2016 57 1364 1376 10.1093/pcp/pcw076 27081099 30. Bae Y.S. Oh H. Rhee S.G. Yoo Y. Do Regulation of reactive oxygen species generation in cell signaling Mol. Cells 2011 32 491 509 10.1007/s10059-011-0276-3 22207195 31. Tejero J. Shiva S. Gladwin M.T. Sources of vascular nitric oxide and reactive oxygen species and their regulation Physiol. Rev. 2019 99 311 379 10.1152/physrev.00036.2017 30379623 32. Chelombitko M.A. Role of Reactive Oxygen Species in Inflammation: A Minireview Mosc. Univ. Biol. Sci. Bull. 2018 73 199 202 10.3103/S009639251804003X 33. Segal B.H. Grimm M.J. Khan A.N.H. Han W. Blackwell T.S. Regulation of innate immunity by NADPH oxidase Free Radic. Biol. Med. 2012 53 72 80 10.1016/j.freeradbiomed.2012.04.022 22583699 34. Mittal M. Siddiqui M.R. Tran K. Reddy S.P. Malik A.B. Reactive oxygen species in inflammation and tissue injury Antioxid. Redox Signal. 2014 20 1126 1167 10.1089/ars.2012.5149 23991888 35. van der Vliet A. Danyal K. Heppner D.E. Dual oxidase: A novel therapeutic target in allergic disease Br. J. Pharmacol. 2018 175 1401 1418 10.1111/bph.14158 29405261 36. Yang H.T. Huang Y.H. Yang G.W. Mini review: Immunologic functions of dual oxidases in mucosal systems of vertebrates Braz. J. Biol. 2019 10.1590/1519-6984.208749 31778477 37. Fischer H. Mechanisms and function of DUOX in epithelia of the lung Antioxid. Redox Signal. 2009 11 2453 2465 10.1089/ars.2009.2558 19358684 38. Hu L. Zachariae E.D. Larsen U.G. Vilhardt F. Petersen S.V. The dynamic uptake and release of SOD3 from intracellular stores in macrophages modulates the inflammatory response Redox Biol. 2019 26 101268 10.1016/j.redox.2019.101268 31326693 39. Kinnula V.L. Crapo J.D. Superoxide dismutases in the lung and human lung diseases Am. J. Respir. Crit. Care Med. 2003 167 1600 1619 10.1164/rccm.200212-1479SO 12796054 40. Ganguly K. Depner M. Fattman C. Bein K. Oury T.D. Wesselkamper S.C. Borchers M.T. Schreiber M. Gao F. Von Mutius E. Superoxide dismutase 3, extracellular (SOD3) variants and lung function Physiol. Genom. 2009 37 260 267 10.1152/physiolgenomics.90363.2008 41. Petersen S.V. Enghild J.J. Extracellular superoxide dismutase: Structural and functional considerations of a protein shaped by two different disulfide bridge patterns Biomed. Pharmacother. 2005 59 175 182 10.1016/j.biopha.2005.03.010 15862712 42. Rahman I. Biswas S.K. Kode A. Oxidant and antioxidant balance in the airways and airway diseases Eur. J. Pharmacol. 2006 533 222 239 10.1016/j.ejphar.2005.12.087 16500642 43. Han W. Fessel J.P. Sherrill T. Kocurek E.G. Yull F.E. Blackwell T.S. Enhanced Expression of Catalase in Mitochondria Modulates NF-κB–Dependent Lung Inflammation through Alteration of Metabolic Activity in Macrophages J. Immunol. 2020 205 1125 1134 10.4049/jimmunol.1900820 32601098 44. Yatmaz S. Seow H.J. Gualano R.C. Wong Z.X. Stambas J. Selemidis S. Crack P.J. Bozinovski S. Anderson G.P. Vlahos R. Glutathione peroxidase-1 reduces influenza A virus-induced lung inflammation Am. J. Respir. Cell Mol. Biol. 2013 48 17 26 10.1165/rcmb.2011-0345OC 23002098 45. Elko E.A. Cunniff B. Seward D.J. Chia S.B. Aboushousha R. Van De Wetering C. Van Der Velden J. Manuel A. Shukla A. Heintz N.H. Peroxiredoxins and Beyond; Redox Systems Regulating Lung Physiology and Disease Antioxid. Redox Signal. 2019 31 1070 1091 10.1089/ars.2019.7752 30799628 46. Schremmer B. Manevich Y. Feinstein S.I. Fisher A.B. Peroxiredoxins in the lung with emphasis on peroxiredoxin VI Subcell. Biochem. 2007 44 317 344 18084901 47. Kinnula V.L. Lehtonen S. Kaarteenaho-Wiik R. Lakari E. Pääkkö P. Kang S.W. Rhee S.G. Soini Y. Cell specific expression of peroxiredoxins in human lung and pulmonary sarcoidosis Thorax 2002 57 157 164 10.1136/thorax.57.2.157 11828047 48. Park J.H. Kim Y.S. Lee H.L. Shim J.Y. Lee K.S. Oh Y.J. Shin S.S. Choi Y.H. Park K.J. Park R.W. Expression of peroxiredoxin and thioredoxin in human lung cancer and paired normal lung Respirology 2006 11 269 275 10.1111/j.1440-1843.2006.00849.x 16635084 49. Xu J. Li T. Wu H. Xu T. Role of thioredoxin in lung disease Pulm. Pharmacol. Ther. 2012 25 154 162 10.1016/j.pupt.2012.01.002 22293327 50. Netto L.E.S. Antunes F. The Roles of peroxiredoxin and thioredoxin in hydrogen peroxide sensing and in signal transduction Mol. Cells 2016 39 65 71 26813662 51. Nakamura T. Nakamura H. Hoshino T. Ueda S. Wada H. Yodoi J. Redox regulation of lung inflammation by thioredoxin Antioxid. Redox Signal. 2005 7 60 71 10.1089/ars.2005.7.60 15650396 52. Shao R. Yang Y. Zhang Y. Zhao S. Zheng Z. Chen G. The expression of thioredoxin-1 and inflammatory cytokines in patients with sepsis Immunopharmacol. Immunotoxicol. 2020 42 280 285 10.1080/08923973.2020.1755309 32326777 53. Janssen-Heininger Y. Glutathione, Glutaredoxin And S-Glutathionylation In Lung Disease Free Radic. Biol. Med. 2017 112 3 10.1016/j.freeradbiomed.2017.10.350 54. Chia S.B. Elko E.A. Aboushousha R. Manuel A.M. van de Wetering C. Druso J.E. van der Velden J. Seward D.J. Anathy V. Irvin C.G. Dysregulation of the glutaredoxin/S-glutathionylation redox axis in lung diseases Am. J. Physiol. Cell Physiol. 2020 318 C304 C327 10.1152/ajpcell.00410.2019 31693398 55. Hemilä H. Louhiala P. Vitamin C may affect lung infections J. R. Soc. Med. 2007 100 495 498 10.1177/014107680710001109 18048704 56. Shaheen S.O. Antioxidants and respiratory disease: The uric acid paradox Thorax 2014 69 978 979 10.1136/thoraxjnl-2014-205751 25122087 57. Fitzpatrick A.M. Jones D.P. Brown L.A.S. Glutathione redox control of asthma: From molecular mechanisms to therapeutic opportunities Antioxid. Redox Signal. 2012 17 375 408 10.1089/ars.2011.4198 22304503 58. Gould N.S. Min E. Gauthier S. Martin R.J. Day B.J. Lung glutathione adaptive responses to cigarette smoke exposure Respir. Res. 2011 12 133 10.1186/1465-9921-12-133 21982222 59. Miyazawa T. Burdeos G.C. Itaya M. Nakagawa K. Miyazawa T. Vitamin E: Regulatory Redox Interactions IUBMB Life 2019 71 430 441 10.1002/iub.2008 30681767 60. Cross C.E. van der Vliet A. O’Neill C.A. Louie S. Halliwell B. Oxidants, antioxidants, and respiratory tract lining fluids Environ. Health Perspect. 1994 102 185 191 61. Behndig A.F. Blomberg A. Helleday R. Duggan S.T. Kelly F.J. Mudway I.S. Antioxidant responses to acute ozone challenge in the healthy human airway Inhal. Toxicol. 2009 21 933 942 10.1080/08958370802603789 19459773 62. Mudway I.S. Blomberg A. Frew A.J. Holgate S.T. Sandström T. Kelly F.J. Antioxidant consumption and repletion kinetics in nasal lavage fluid following exposure of healthy human volunteers to ozone Eur. Respir. J. 1999 13 1429 1438 10.1183/09031936.99.13614399 10445623 63. Barthelemy J. Sanchez K. Miller M.R. Khreis H. New opportunities to mitigate the burden of disease caused by traffic related air pollution: Antioxidant-rich diets and supplements Int. J. Environ. Res. Public Health 2020 17 630 10.3390/ijerph17020630 31963738 64. Ballinger C.A. Cueto R. Squadrito G. Coffin J.F. Velsor L.W. Pryor W.A. Postlethwait E.M. Antioxidant-mediated augmentation of ozone-induced membrane oxidation Free Radic. Biol. Med. 2005 38 515 526 10.1016/j.freeradbiomed.2004.11.009 15649654 65. Cho H.Y. Reddy S.P. Kleeberger S.R. Nrf2 defends the lung from oxidative stress Antioxid. Redox Signal. 2006 8 76 87 10.1089/ars.2006.8.76 16487040 66. Kavian N. Mehlal S. Jeljeli M. Saidu N.E.B. Nicco C. Cerles O. Chouzenoux S. Cauvet A. Camus C. Ait-Djoudi M. The Nrf2-antioxidant response element signaling pathway controls fibrosis and autoimmunity in scleroderma Front. Immunol. 2018 9 1896 10.3389/fimmu.2018.01896 30177933 67. Müller T. Hengstermann A. Nrf2: Friend and Foe in preventing cigarette smoking-dependent lung disease Chem. Res. Toxicol. 2012 25 1805 1824 10.1021/tx300145n 22686525 68. Osburn W.O. Kensler T.W. Nrf2 signaling: An adaptive response pathway for protection against environmental toxic insults Mutat. Res. Rev. Mutat. Res. 2008 659 31 39 10.1016/j.mrrev.2007.11.006 69. Aghasafari P. George U. Pidaparti R. A review of inflammatory mechanism in airway diseases Inflamm. Res. 2019 68 59 74 10.1007/s00011-018-1191-2 30306206 70. Park H.S. Kim S.R. Lee Y.C. Impact of oxidative stress on lung diseases Respirology 2009 14 27 38 10.1111/j.1440-1843.2008.01447.x 19144046 71. Matthay M.A. Zemans R.L. Zimmerman G.A. Arabi Y.M. Beitler J.R. Mercat A. Herridge M. Randolph A.G. Calfee C.S. Acute respiratory distress syndrome Nat. Rev. Dis. Prim. 2018 5 18 10.1038/s41572-019-0069-0 72. Fernando S.M. Cardinal P. Brindley P.G. Hypoxemic Respiratory Failure from Acute Respiratory Distress Syndrome Secondary to Leptospirosis Case Rep. Crit. Care 2017 2017 1 4 10.1155/2017/9062107 73. Ashbaugh D.G. Bigelow D.B. Petty T.L. Levine B.E. Acute respiratory distress in adults Lancet 1967 2 319 323 10.1016/S0140-6736(67)90168-7 4143721 74. Ranieri V.M. Rubenfeld G.D. Thompson B.T. Ferguson N.D. Caldwell E. Fan E. Camporota L. Slutsky A.S. Acute respiratory distress syndrome: The Berlin definition JAMA J. Am. Med. Assoc. 2012 307 2526 2533 75. Cardinal-Fernandez P. Lorente J.A. Ballen-Barragan A. Matute-Bello G. Acute respiratory distress syndrome and diffuse alveolar damage new insights on a complex relationship Ann. Am. Thorac. Soc. 2017 14 844 850 10.1513/AnnalsATS.201609-728PS 28570160 76. Chiumello D. Coppola S. Froio S. Gotti M. What’s next after ARDS: Long-term outcomes Respir. Care 2016 61 689 699 10.4187/respcare.04644 27121623 77. Fanelli V. Ranieri V.M. Mechanisms and clinical consequences of acute lung injury Ann. Am. Thorac. Soc. 2015 12 S3 S8 10.1513/AnnalsATS.201407-340MG 25830831 78. Kellner M. Noonepalle S. Lu Q. Srivastava A. Zemskov E. Black S.M. ROS signaling in the pathogenesis of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) Advances in Experimental Medicine and Biology Springer New York, NY, USA 2017 Volume 967 105 137 79. Zemans R.L. Matthay M.A. What drives neutrophils to the alveoli in ARDS? Thorax 2017 72 1 3 10.1136/thoraxjnl-2016-209170 27974631 80. Potey P.M. Rossi A.G. Lucas C.D. Dorward D.A. Neutrophils in the initiation and resolution of acute pulmonary inflammation: Understanding biological function and therapeutic potential J. Pathol. 2019 247 672 685 10.1002/path.5221 30570146 81. Allardet-Servent J. Forel J.M. Roch A. Guervilly C. Chiche L. Castanier M. Embriaco N. Gainnier M. Papazian L. Fio2 and acute respiratory distress syndrome definition during lung protective ventilation Crit. Care Med. 2009 37 202 207 10.1097/CCM.0b013e31819261db 19050631 82. Bellani G. Laffey J.G. Pham T. Madotto F. Fan E. Brochard L. Esteban A. Gattinoni L. Bumbasirevic V. Piquilloud L. Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome: Insights from the LUNG SAFE Study Am. J. Respir. Crit. Care Med. 2017 195 67 77 10.1164/rccm.201606-1306OC 27753501 83. Elicker B.M. Jones K.T. Naeger D.M. Frank J.A. Imaging of Acute Lung Injury Radiol. Clin. N. Am. 2016 54 1119 1132 10.1016/j.rcl.2016.05.006 27719979 84. Pesenti A. Musch G. Lichtenstein D. Mojoli F. Amato M.B.P. Cinnella G. Gattinoni L. Quintel M. Imaging in acute respiratory distress syndrome Intensive Care Med. 2016 42 686 698 10.1007/s00134-016-4328-1 27033882 85. Rodrigues R.S. Bozza F.A. Hanrahan C.J. Wang L.M. Wu Q. Hoffman J.M. Zimmerman G.A. Morton K.A. 18F-fluoro-2-deoxyglucose PET informs neutrophil accumulation and activation in lipopolysaccharide-induced acute lung injury Nucl. Med. Biol. 2017 48 52 62 10.1016/j.nucmedbio.2017.01.005 28237630 86. Ma Y. Ge A. Zhu W. Liu Y.N. Ji N.F. Zha W.J. Zhang J.X. Zeng X.N. Huang M. Morin attenuates ovalbumin-induced airway inflammation by modulating oxidative stress-responsive MAPK signaling Oxid. Med. Cell. Longev. 2016 2016 5843672 10.1155/2016/5843672 26783416 87. Lee K.Y. Pneumonia, acute respiratory distress syndrome, and early immune-modulator therapy Int. J. Mol. Sci. 2017 18 388 10.3390/ijms18020388 88. Keddissi J.I. Youness H.A. Jones K.R. Kinasewitz G.T. Fluid management in Acute Respiratory Distress Syndrome: A narrative review Can. J. Respir. Ther. 2019 50 1 8 10.29390/cjrt-2018-016 89. Quirt J. Hildebrand K.J. Mazza J. Noya F. Kim H. Asthma Allergy Asthma Clin. Immunol. 2018 14 50 10.1186/s13223-018-0279-0 30275843 90. Mims J.W. Asthma: Definitions and pathophysiology Int. Forum Allergy Rhinol. 2015 5 S2 S6 10.1002/alr.21609 26335832 91. Bush A. Pathophysiological mechanisms of asthma Front. Pediatr. 2019 7 68 10.3389/fped.2019.00068 30941334 92. Fahy J.V. Type 2 inflammation in asthma-present in most, absent in many Nat. Rev. Immunol. 2015 15 57 65 10.1038/nri3786 25534623 93. Teran L.M. CCL chemokines and asthma Immunol. Today 2000 21 235 242 10.1016/S0167-5699(00)01634-0 10782055 94. Xue L. Fergusson J. Salimi M. Panse I. Ussher J.E. Hegazy A.N. Vinall S.L. Jackson D.G. Hunter M.G. Pettipher R. Prostaglandin D2 and leukotriene E4 synergize to stimulate diverse TH2 functions and TH2 cell/neutrophil crosstalk J. Allergy Clin. Immunol. 2015 135 1358 1366.e11 10.1016/j.jaci.2014.09.006 25441644 95. Wu D. Zhou J. Bi H. Li L. Gao W. Huang M. Adcock I.M. Barnes P.J. Yao X. CCL11 as a potential diagnostic marker for asthma? J. Asthma 2014 51 847 854 10.3109/02770903.2014.917659 24796647 96. McBrien C.N. Menzies-Gow A. The biology of eosinophils and their role in asthma Front. Med. 2017 4 93 10.3389/fmed.2017.00093 28713812 97. Bowler R.P. Crapo J.D. Oxidative stress in allergic respiratory diseases J. Allergy Clin. Immunol. 2002 110 349 356 10.1067/mai.2002.126780 12209079 98. Mishra V. Banga J. Silveyra P. Oxidative stress and cellular pathways of asthma and inflammation: Therapeutic strategies and pharmacological targets Pharmacol. Ther. 2018 181 169 182 10.1016/j.pharmthera.2017.08.011 28842273 99. Antczak A. Kurmanowska Z. Kasielski M. Nowak D. Inhaled glucocorticosteroids decrease hydrogen peroxide level in expired air condensate in asthmatic patients Respir. Med. 2000 94 416 421 10.1053/rmed.1999.0801 10868702 100. Sahiner U.M. Birben E. Erzurum S. Sackesen C. Kalayci O. Oxidative stress in asthma World Allergy Organ. J. 2011 4 151 158 10.1097/WOX.0b013e318232389e 23268432 101. Gerke A.K. Hunninghake G. The Immunology of Sarcoidosis Clin. Chest Med. 2008 29 379 390 10.1016/j.ccm.2008.03.014 18539233 102. Lan N. Luo G. Yang X. Cheng Y. Zhang Y. Wang X. Wang X. Xie T. Li G. Liu Z. 25-hydroxyvitamin D3-deficiency enhances oxidative stress and corticosteroid resistance in severe asthma exacerbation PLoS ONE 2014 9 e111599 10.1371/journal.pone.0111599 25380286 103. Dworski R. Oxidant stress in asthma Thorax 2000 55 S51 S53 10.1136/thorax.55.suppl_2.S51 10992559 104. Arora P. Ansari S.H. Role of Various Mediators in Inflammation of Asthmatic Airways Asthma—Biological Evidences IntechOpen London, UK 2019 105. Qu J. Li Y. Zhong W. Gao P. Hu C. Recent developments in the role of reactive oxygen species in allergic asthma J. Thorac. Dis. 2017 9 E32 E43 10.21037/jtd.2017.01.05 28203435 106. Henricks P.A.J. Nijkamp F.P. Reactive oxygen species as mediators in asthma Pulm. Pharmacol. Ther. 2001 14 409 421 10.1006/pupt.2001.0319 11782121 107. Lambrecht B.N. Hammad H. Fahy J.V. The Cytokines of Asthma Immunity 2019 50 975 991 10.1016/j.immuni.2019.03.018 30995510 108. Rambacher K.M. Moniri N.H. The β2-adrenergic receptor-ROS signaling axis: An overlooked component of β2AR function? Biochem. Pharmacol. 2020 171 113690 10.1016/j.bcp.2019.113690 31697929 109. Llano-Diez M. Sinclair J. Yamada T. Zong M. Fauconnier J. Zhang S.J. Katz A. Jardemark K. Westerblad H. Andersson D.C. The role of reactive oxygen species in β-adrenergic signaling in cardiomyocytes from mice with the metabolic syndrome PLoS ONE 2016 11 e0167090 10.1371/journal.pone.0167090 27907040 110. Song X. Zhao C. Dai C. Ren Y. An N. Wen H. Pan L. Cheng M. Zhang Y. Suppression of the increasing level of acetylcholine-stimulated intracellular Ca2+ in guinea pig airway smooth muscle cells by mabuterol Biomed. Rep. 2015 3 778 786 10.3892/br.2015.502 26623015 111. Tang W. Role of Airway Smooth Muscle Cells in Asthma Pathology Asthma—Biological Evidences IntechOpen London, UK 2019 112. Jesenak M. Zelieskova M. Babusikova E. Oxidative stress and bronchial asthma in children-causes or consequences? Front. Pediatr. 2017 5 162 10.3389/fped.2017.00162 28791280 113. Cho Y.S. Moon H.B. The role of oxidative stress in the pathogenesis of asthma Allergy Asthma Immunol. Res. 2010 2 183 187 10.4168/aair.2010.2.3.183 20592917 114. Rao R. Oxidative stress-induced disruption of epithelial and endothelial tight junctions Front. Biosci. 2008 13 7210 7226 10.2741/3223 18508729 115. He P. Talukder M.A.H. Gao F. Oxidative Stress and Microvessel Barrier Dysfunction Front. Physiol. 2020 11 472 10.3389/fphys.2020.00472 32536875 116. Wan W.Y.H. Hollins F. Haste L. Woodman L. Hirst R.A. Bolton S. Gomez E. Sutcliffe A. Desai D. Chachi L. NADPH Oxidase-4 Overexpression Is Associated with Epithelial Ciliary Dysfunction in Neutrophilic Asthma Chest 2016 149 1445 1459 10.1016/j.chest.2016.01.024 26836936 117. Nociari M. Ocheretina O. Schoggins J.W. Falck-Pedersen E. Sensing Infection by Adenovirus: Toll-Like Receptor-Independent Viral DNA Recognition Signals Activation of the Interferon Regulatory Factor 3 Master Regulator J. Virol. 2007 81 4145 4157 10.1128/JVI.02685-06 17251283 118. Guillot L. Le Goffic R. Bloch S. Escriou N. Akira S. Chignard M. Si-Tahar M. Involvement of Toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus J. Biol. Chem. 2005 280 5571 5580 10.1074/jbc.M410592200 15579900 119. Diebold S.S. Kaisho T. Hemmi H. Akira S. Reis E Sousa C. Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA Science 2004 303 1529 1531 10.1126/science.1093616 14976261 120. Kurt-Jones E.A. Popova L. Kwinn L. Haynes L.M. Jones L.P. Tripp R.A. Walsh E.E. Freeman M.W. Golenbock D.T. Anderson L.J. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus Nat. Immunol. 2000 1 398 401 10.1038/80833 11062499 121. Yao H. Yang S.R. Kode A. Rajendrasozhan S. Caito S. Adenuga O. Henry R. Edirisinghe I. Rahman I. Redox regulation of lung inflammation: Role of NADPH oxidase and NF-κB signalling Biochem. Soc. Trans. 2007 35 1151 1155 10.1042/BST0351151 17956299 122. Woodland D.L. Cell-mediated immunity to respiratory virus infections Curr. Opin. Immunol. 2003 15 430 435 10.1016/S0952-7915(03)00067-0 12900275 123. Barrera-Mendoza C.C. Ayala-Mata F. Cortés-Rojo C. García-Pérez M.E. Rodríguez-Orozco A.R. Vitaminas antioxidantes en asma Rev. Alerg. México 2018 65 61 10.29262/ram.v65i1.306 124. Comhair S. Khan A. Erzurum S. Superoxide dismutase as a longitudinal biomarker of lung function in asthma Eur. Respir. J. 2011 38 125. Janssen-Heininger Y. Ckless K. Reynaert N. Van Der Vliet A. SOD inactivation in asthma: Bad news or NO news? Am. J. Pathol. 2005 166 649 652 10.1016/S0002-9440(10)62286-9 15743777 126. Endaryanto A. Hikmah Z. Harsono A. The use of superoxide dismutase in accelerating symptom relief in asthmatic and house dust mite allergic children receiving house dust mite immunotherapy: Double blind randomized controlled clinical trial Int. J. Integr. Health Sci. 2015 3 72 78 10.15850/ijihs.v3n2.587 127. Ghosh S. Willard B. Comhair S.A.A. Dibello P. Xu W. Shiva S. Aulak K.S. Kinter M. Erzurum S.C. Disulfide bond as a switch for copper-zinc superoxide dismutase activity in asthma Antioxid. Redox Signal. 2013 18 412 423 10.1089/ars.2012.4566 22867017 128. Pittet J.F. Griffiths M.J.D. Geiser T. Kaminski N. Dalton S.L. Huang X. Brown L.A.S. Gotwals P.J. Koteliansky V.E. Matthay M.A. TGF-β is a critical mediator of acute lung injury J. Clin. Investig. 2001 107 1537 1544 10.1172/JCI11963 11413161 129. Comhair S.A.A. Xu W. Ghosh S. Thunnissen F.B.J.M. Almasan A. Calhoun W.J. Janocha A.J. Zheng L. Hazen S.L. Erzurum S.C. Superoxide dismutase inactivation in pathophysiology of asthmatic airway remodeling and reactivity Am. J. Pathol. 2005 166 663 674 10.1016/S0002-9440(10)62288-2 15743779 130. Comhair S.A.A. Erzurum S.C. Redox control of asthma: Molecular mechanisms and therapeutic opportunities Antioxid. Redox Signal. 2010 12 93 124 10.1089/ars.2008.2425 19634987 131. Ghosh S. Janocha A.J. Aronica M.A. Swaidani S. Comhair S.A.A. Xu W. Zheng L. Kaveti S. Kinter M. Hazen S.L. Nitrotyrosine Proteome Survey in Asthma Identifies Oxidative Mechanism of Catalase Inactivation J. Immunol. 2006 176 5587 5597 10.4049/jimmunol.176.9.5587 16622028 132. Bozinovski S. Seow H.J. Crack P.J. Anderson G.P. Vlahos R. Glutathione peroxidase-1 primes pro-inflammatory cytokine production after LPS challenge in vivo PLoS ONE 2012 7 e33172 10.1371/journal.pone.0033172 22412999 133. Won H.Y. Sohn J.H. Min H.J. Lee K. Woo H.A. Ho Y.S. Park J.W. Rhee S.G. Hwang E.S. Glutathione peroxidase 1 deficiency attenuates allergen-induced airway inflammation by suppressing th2 and th17 cell development Antioxid. Redox Signal. 2010 13 575 587 10.1089/ars.2009.2989 20367278 134. Iorio A. Velocci M. Graziano M.E. Piacentini S. Polimanti R. Manfellotto D. Fuciarelli M. GPX1*Pro198Leu AND GPX3 rs2070593 as genetic risk markers for Italian asthmatic patients Clin. Exp. Pharmacol. Physiol. 2016 43 277 279 10.1111/1440-1681.12522 26662676 135. Comhair S.A.A. Erzurum S.C. The regulation and role of extracellular glutathione peroxidase Antioxid. Redox Signal. 2005 7 72 79 10.1089/ars.2005.7.72 15650397 136. Callister M.E. Burke-Gaffney A. Quinlan G.J. Nicholson A.G. Florio R. Nakamura H. Yodoi J. Evans T.W. Extracellular thioredoxin levels are increased in patients with acute lung injury Thorax 2006 61 521 527 10.1136/thx.2005.053041 16601094 137. Yamada Y. Nakamura H. Adachi T. Sannohe S. Oyamada H. Kayaba H. Yodoi J. Chihara J. Elevated serum levels of thioredoxin in patients with acute exacerbation of asthma Immunol. Lett. 2003 86 199 205 10.1016/S0165-2478(03)00006-3 12644323 138. Aesif S.W. Anathy V. Kuipers I. Guala A.S. Reiss J.N. Ho Y.S. Janssen-Heininger Y.M.W. Ablation of glutaredoxin-1 attenuates lipopolysaccharide-induced lung inflammation and alveolar macrophage activation Am. J. Respir. Cell Mol. Biol. 2011 44 491 499 10.1165/rcmb.2009-0136OC 20539014 139. Kuipers I. Louis R. Manise M. Dentener M.A. Irvin C.G. Janssen-Heininger Y.M.W. Brightling C.E. Wouters E.F.M. Reynaert N.L. Increased glutaredoxin-1 and decreased protein S-glutathionylation in sputum of asthmatics Eur. Respir. J. 2013 41 469 472 10.1183/09031936.00115212 23370801 140. Hoffman S.M. Tully J.E. Lahue K.G. Anathy V. Nolin J.D. Guala A.S. van der Velden J.L.J. Ho Y.S. Aliyeva M. Daphtary N. Genetic ablation of glutaredoxin-1 causes enhanced resolution of airways hyperresponsiveness and mucus metaplasia in mice with allergic airways disease Am. J. Physiol. Lung Cell. Mol. Physiol. 2012 303 L528 L538 10.1152/ajplung.00167.2012 22752969 141. Chung S. Sundar I.K. Yao H. Ho Y.S. Rahman I. Glutaredoxin 1 regulates cigarette smoke-mediated lung inflammation through differential modulation of IκB kinases in mice: Impact on histone acetylation Am. J. Physiol. Lung Cell. Mol. Physiol. 2010 299 L192 L203 10.1152/ajplung.00426.2009 20472709 142. Kuipers I. Bracke K.R. Brusselle G.G. Aesif S.W. Krijgsman R. Arts I.C. Wouters E.F.M. Reynaert N.L. Altered cigarette smoke-induced lung inflammation due to Ablation of Grx1 PLoS ONE 2012 7 e38984 10.1371/journal.pone.0038984 22723915 143. Hoffman S. Nolin J. McMillan D. Wouters E. Janssen-Heininger Y. Reynaert N. Thiol redox chemistry: Role of protein cysteine oxidation and altered redox homeostasis in allergic inflammation and asthma J. Cell. Biochem. 2015 116 884 892 10.1002/jcb.25017 25565397 144. Fitzpatrick A.M. Stephenson S.T. Hadley G.R. Burwell L. Penugonda M. Simon D.M. Hansen J. Jones D.P. Brown L.A.S. Thiol redox disturbances in children with severe asthma are associated with posttranslational modification of the transcription factor nuclear factor (erythroid-derived 2)-like 2 J. Allergy Clin. Immunol. 2011 127 1604 1611 10.1016/j.jaci.2011.03.031 21514635 145. Malhotra D. Thimmulappa R. Navas-Acien A. Sandford A. Elliott M. Singh A. Chen L. Zhuang X. Hogg J. Pare P. Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1 Am. J. Respir. Crit. Care Med. 2008 178 592 604 10.1164/rccm.200803-380OC 18556627 146. Liu Q. Gao Y. Ci X. Role of Nrf2 and its activators in respiratory diseases Oxid. Med. Cell. Longev. 2019 2019 10.1155/2019/7090534 30728889 147. Fergeson J.E. Patel S.S. Lockey R.F. Fla T. Acute asthma, prognosis, and treatment J. Allergy Clin. Immunol. 2017 139 438 447 10.1016/j.jaci.2016.06.054 27554811 148. Castillo J.R. Peters S.P. Busse W.W. Asthma Exacerbations: Pathogenesis, Prevention, and Treatment J. Allergy Clin. Immunol. Pract. 2017 5 918 927 10.1016/j.jaip.2017.05.001 28689842 149. Keskin O. Uluca Ü. Birben E. Coşkun Y. Ozkars M.Y. Keskin M. Kucukosmanoglu E. Kalayci O. Genetic associations of the response to inhaled corticosteroids in children during an asthma exacerbation Pediatr. Allergy Immunol. 2016 27 507 513 10.1111/pai.12566 27003716 150. Ökrös Z. Endreffy E. Novak Z. Maroti Z. Monostori P. Varga I.S. Király A. Turi S. Changes in NADPH oxidase mRNA level can be detected in blood at inhaled corticosteroid treated asthmatic children Life Sci. 2012 91 907 911 10.1016/j.lfs.2012.08.039 22982469 151. Tashkin D.P. Lipworth B. Brattsand R. Benefit:Risk Profile of Budesonide in Obstructive Airways Disease Drugs 2019 79 1757 1775 10.1007/s40265-019-01198-7 31549299 152. Gibson P.G. Saltos N. Borgas T. Airway mast cells and eosinophils correlate with clinical severity and airway hyperresponsiveness in corticosteroid-treated asthma J. Allergy Clin. Immunol. 2000 105 752 759 10.1067/mai.2000.105319 10756226 153. Brightling C.E. Green R.H. Pavord I.D. Biomarkers predicting response to corticosteroid therapy in asthma Treat. Respir. Med. 2005 4 309 316 10.2165/00151829-200504050-00002 16137188 154. Austin D. Pouliquen I. Keene O. Yancey S. Blood eosinophil dose response to oral corticosteroids in a population of patients with severe asthma Eur. Respir. J. 2016 48 PA1110 155. Domingo C. Rello J. Sogo A. As-needed ICS-LABA in Mild Asthma: What Does the Evidence Say? Drugs 2019 79 1729 1737 10.1007/s40265-019-01202-0 31584145 156. Johnston N.W. Mandhane P.J. Dai J. Duncan J.M. Greene J.M. Lambert K. Sears M.R. Attenuation of the September epidemic of asthma exacerbations in children: A randomized, controlled trial of montelukast added to usual therapy Pediatrics 2007 120 e702 e712 10.1542/peds.2006-3317 17766511 157. Vogelberg C. Szefler S.J. Vrijlandt E.J.L.E. Boner A.L. Engel M. El Azzi G. Vulcu S.D. Moroni-Zentgraf P.M. Eickmeier O. Hamelmann E.H. Tiotropium add-on therapy is safe and reduces seasonal worsening in paediatric asthma patients Eur. Respir. J. 2019 53 1801824 10.1183/13993003.01824-2018 31097514 158. Sterling Y.M. Impact of the Environment on Asthma Control J. Community Health Nurs. 2012 29 143 153 10.1080/07370016.2012.697844 22857403 159. Donohue J.F. Wise R. Busse W.W. Garfinkel S. Zubek V.B. Ghafouri M. Manuel R.C. Schlenker-Herceg R. Bleecker E.R. Efficacy and safety of ipratropium bromide/albuterol compared with albuterol in patients with moderate-to-severe asthma: A randomized controlled trial BMC Pulm. Med. 2016 16 65 10.1186/s12890-016-0223-3 27130202 160. Rodrigo G.J. Castro-Rodriguez J.A. Anticholinergics in the treatment of children and adults with acute asthma: A systematic review with meta-analysis Thorax 2005 60 740 746 Erratum in Thorax 2010 , 65 , 1118 10.1136/thx.2005.047803 16055613 161. Zorc J.J. Pusic M.V. Ogborn C.J. Lebet R. Duggan A.K. Ipratropium bromide added to asthma treatment in the pediatric emergency department Pediatrics 1999 103 748 752 10.1542/peds.103.4.748 10103297 162. Rodrigo G.J. Rapid effects of inhaled corticosteroids in acute asthma: An evidence-based evaluation Chest 2006 130 1301 1311 10.1378/chest.130.5.1301 17099004 163. Rowe B.H. Edmonds M.L. Spooner C.H. Diner B. Camargo C.A. Corticosteroid therapy for acute asthma Respir. Med. 2004 98 275 284 10.1016/j.rmed.2003.11.016 15072167 164. Corlateanu A. Mendez Y. Wang Y. de Garnica R.J.A. Botnaru V. Siafakas N. Chronic obstructive pulmonary disease and phenotypes: A state-of-the-art Pulmonology 2020 26 95 100 10.1016/j.pulmoe.2019.10.006 31740261 165. Rovina N. Koutsoukou A. Koulouris N.G. Inflammation and immune response in COPD: Where do we stand? Mediat. Inflamm. 2013 2013 413735 10.1155/2013/413735 166. Donnelly L.E. Barnes P.J. Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease Trends Pharmacol. Sci. 2006 27 546 553 10.1016/j.tips.2006.08.001 16911834 167. Barnes P.J. Cellular and molecular mechanisms of asthma and COPD Clin. Sci. 2017 131 1541 1558 10.1042/CS20160487 28659395 168. Traynor T.R. Herring A.C. Dorf M.E. Kuziel W.A. Toews G.B. Huffnagle G.B. Differential Roles of CC Chemokine Ligand 2/Monocyte Chemotactic Protein-1 and CCR2 in the Development of T1 Immunity J. Immunol. 2002 168 4659 4666 10.4049/jimmunol.168.9.4659 11971015 169. Gilowska I. Kasper Ł. Bogacz K. Szczegielniak J. Szymasek T. Kasper M. Czerwinski M. Sładek K. Majorczyk E. Impact of Matrix Metalloproteinase 9 on COPD Development in Polish Patients: Genetic Polymorphism, Protein Level, and Their Relationship with Lung Function BioMed Res. Int. 2018 2018 6417415 10.1155/2018/6417415 30643813 170. Dey T. Kalita J. Weldon S. Taggart C. Proteases and Their Inhibitors in Chronic Obstructive Pulmonary Disease J. Clin. Med. 2018 7 244 10.3390/jcm7090244 30154365 171. Ponce-Gallegos M.A. Ramírez-Venegas A. Falfán-Valencia R. Th17 profile in COPD exacerbations Int. J. COPD 2017 12 1857 1865 10.2147/COPD.S136592 172. Lane N. Robins R.A. Corne J. Fairclough L. Regulation in chronic obstructive pulmonary disease: The role of regulatory T-cells and Th17 cells Clin. Sci. 2010 119 75 86 10.1042/CS20100033 173. Di Stefano A. Sangiorgi C. Gnemmi I. Casolari P. Brun P. Ricciardolo F.L.M. Contoli M. Papi A. Maniscalco P. Ruggeri P. TGF-β Signaling Pathways in Different Compartments of the Lower Airways of Patients With Stable COPD Chest 2018 153 851 862 10.1016/j.chest.2017.12.017 29289685 174. Verhamme F.M. Bracke K.R. Joos G.F. Brusselle G.G. Transforming growth factor-β superfamily in obstructive lung diseases: More suspects than TGF-β alone Am. J. Respir. Cell Mol. Biol. 2015 52 653 662 10.1165/rcmb.2014-0282RT 25396302 175. Yan F. Gao H. Zhao H. Bhatia M. Zeng Y. Roles of airway smooth muscle dysfunction in chronic obstructive pulmonary disease J. Transl. Med. 2018 16 262 10.1186/s12967-018-1635-z 30257694 176. Zhuan B. Yu Y. Yang Z. Zhao X. Li P. Mechanisms of oxidative stress effects of the NADPH oxidase-ROS-NF-κB transduction pathway and VPO1 on patients with chronic obstructive pulmonary disease combined with pulmonary hypertension Eur. Rev. Med. Pharmacol. Sci. 2017 21 3459 3464 28829513 177. Meijer M. Rijkers G.T. Van Overveld F.J. Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease Expert Rev. Clin. Immunol. 2013 9 1055 1068 10.1586/1744666X.2013.851347 24168412 178. Klimanov I.A. Khaletskaya A. Kuznechov A. Kontorschikova K. Kubysheva N. Leonova D. Bobkova A. Soodaeva S. Lipid peroxidation in patients with COPD and chronic heart failure Eur. Respir. J. 2018 52 PA931 179. Nicks M.E. O’Brien M.M. Bowler R.P. Plasma antioxidants are associated with impaired lung function and COPD exacerbations in smokers COPD J. Chronic Obstr. Pulm. Dis. 2011 8 264 269 10.3109/15412555.2011.579202 21627570 180. Lomas D.A. Does protease-antiprotease imbalance explain Chronic obstructive pulmonary disease? Ann. Am. Thorac. Soc. 2016 13 S130 S137 27115947 181. Fischer B.M. Pavlisko E. Voynow J.A. Pathogenic triad in COPD: Oxidative stress, protease-antiprotease imbalance, and inflammation Int. J. COPD 2011 6 413 421 10.2147/COPD.S10770 182. Turgut T. Ilhan N. Deveci F. Akpolat N. Erden E.S. Muz M.H. Glutathione and nitrite levels in induced sputum at COPD patients and healthy smokers J. Thorac. Dis. 2014 6 765 771 24977001 183. Harju T. Kaarteenaho-Wiik R. Sirviö R. Pääkkö P. Crapo J.D. Oury T.D. Soini Y. Kinnula V.L. Manganese superoxide dismutase is increased in the airways of smokers’ lungs Eur. Respir. J. 2004 24 765 771 10.1183/09031936.04.00121203 15516670 184. McGuinness A. Sapey E. Oxidative Stress in COPD: Sources, Markers, and Potential Mechanisms J. Clin. Med. 2017 6 21 10.3390/jcm6020021 185. Bentley A.R. Emrani P. Cassano P.A. Genetic variation and gene expression in antioxidant related enzymes and risk of COPD: A systematic review Thorax 2008 63 956 961 10.1136/thx.2007.086199 18566111 186. Young R.P. Hopkins R. Black P.N. Eddy C. Wu L. Gamble G.D. Mills G.D. Garrett J.E. Eaton T.E. Rees M.I. Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function Thorax 2006 61 394 399 10.1136/thx.2005.048512 16467073 187. Zhou J.D. Wang C.X. Wu J.L. Fukunaga A. Cheng Z.S. Wang J.Q. Yamauchi A. Yodoi J. Tian H. Anti-allergic and anti-inflammatory effects and molecular mechanisms of thioredoxin on respiratory system diseases Antioxid. Redox Signal. 2020 32 785 801 10.1089/ars.2019.7807 31884805 188. Peltoniemi M.J. Rytilä P.H. Harju T.H. Soini Y.M. Salmenkivi K.M. Ruddock L.W. Kinnula V.L. Modulation of glutaredoxin in the lung and sputum of cigarette smokers and chronic obstructive pulmonary disease Respir. Res. 2006 7 133 10.1186/1465-9921-7-133 17064412 189. Estornut C. Roger I. Ballester B. Ribera P. Cortijo J. Activation of nuclear factor erythroid 2-related (Nrf2) system as a novel therapeutic approach in COPD Eur. Respir. J. 2019 54 PA4216 190. Okpechi S.C. Ghonim M.A. Lammi M.R. Advances in chronic obstructive pulmonary disease therapy: A vascular-targeted approach Clin. Med. Insights Ther. 2017 9 1179559X1771912 10.1177/1179559X17719127 191. Vogelmeier C.F. Criner G.J. Martinez F.J. Anzueto A. Barnes P.J. Bourbeau J. Celli B.R. Chen R. Decramer M. Fabbri L.M. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report. GOLD Executive Summary Am. J. Respir. Crit. Care Med. 2017 195 557 582 10.1164/rccm.201701-0218PP 28128970 192. Barratt S. Creamer A. Hayton C. Chaudhuri N. Idiopathic Pulmonary Fibrosis (IPF): An Overview J. Clin. Med. 2018 7 201 10.3390/jcm7080201 193. Futosi K. Fodor S. Mócsai A. Neutrophil cell surface receptors and their intracellular signal transduction pathways Int. Immunopharmacol. 2013 17 638 650 10.1016/j.intimp.2013.06.034 23994464 194. Mayadas T.N. Cullere X. Lowell C.A. The multifaceted functions of neutrophils Annu. Rev. Pathol. Mech. Dis. 2014 9 181 218 10.1146/annurev-pathol-020712-164023 195. Mills C.D. M1 and M2 macrophages: Oracles of health and disease Crit. Rev. Immunol. 2012 32 463 488 10.1615/CritRevImmunol.v32.i6.10 23428224 196. Schupp J.C. Binder H. Jäger B. Cillis G. Zissel G. Müller-Quernheim J. Prasse A. Macrophage activation in acute exacerbation of idiopathic pulmonary fibrosis PLoS ONE 2015 10 e0116775 10.1371/journal.pone.0116775 25590613 197. Misharin A.V. Morales-Nebreda L. Reyfman P.A. Cuda C.M. Walter J.M. McQuattie-Pimentel A.C. Chen C.I. Anekalla K.R. Joshi N. Williams K.J.N. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span J. Exp. Med. 2017 214 2387 2404 10.1084/jem.20162152 28694385 198. Kreuter M. Maher T.M. Can monocytes predict prognosis of idiopathic pulmonary fibrosis? Lancet Respir. Med. 2019 7 467 469 10.1016/S2213-2600(19)30050-5 30935880 199. Desai O. Winkler J. Minasyan M. Herzog E.L. The role of immune and inflammatory cells in idiopathic pulmonary fibrosis Front. Med. 2018 5 43 10.3389/fmed.2018.00043 29616220 200. Heukels P. van Hulst J.A.C. van Nimwegen M. Boorsma C.E. Melgert B.N. van den Toorn L.M. Boomars K.A.T. Wijsenbeek M.S. Hoogsteden H. von der Thüsen J.H. Fibrocytes are increased in lung and peripheral blood of patients with idiopathic pulmonary fibrosis Respir. Res. 2018 19 90 10.1186/s12931-018-0798-8 29747640 201. Maharaj S. Shimbori C. Kolb M. Fibrocytes in pulmonary fibrosis: A brief synopsis Eur. Respir. Rev. 2013 22 552 557 10.1183/09059180.00007713 24293471 202. Overed-Sayer C. Rapley L. Mustelin T. Clarke D.L. Are mast cells instrumental for fibrotic diseases? Front. Pharmacol. 2014 4 174 10.3389/fphar.2013.00174 24478701 203. Komi D.E.A. Mortaz E. Amani S. Tiotiu A. Folkerts G. Adcock I.M. The Role of Mast Cells in IgE-Independent Lung Diseases Clin. Rev. Allergy Immunol. 2020 58 377 387 10.1007/s12016-020-08779-5 32086776 204. Marchal-Sommé J. Uzunhan Y. Marchand-Adam S. Valeyre D. Soumelis V. Crestani B. Soler P. Cutting Edge: Nonproliferating Mature Immune Cells Form a Novel Type of Organized Lymphoid Structure in Idiopathic Pulmonary Fibrosis J. Immunol. 2006 176 5735 5739 10.4049/jimmunol.176.10.5735 16670278 205. Nuovo G.J. Hagood J.S. Magro C.M. Chin N. Kapil R. Davis L. Marsh C.B. Folcik V.A. The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis Mod. Pathol. 2012 25 416 433 10.1038/modpathol.2011.166 22037258 206. Todd N.W. Scheraga R.G. Galvin J.R. Iacono A.T. James Britt E. Luzina I.G. Burke A.P. Atamas S.P. Lymphocyte aggregates persist and accumulate in the lungs of patients with idiopathic pulmonary fibrosis J. Inflamm. Res. 2013 6 63 70 10.2147/JIR.S40673 23576879 207. Wynn T.A. Fibrotic disease and the TH1/TH2 paradigm Nat. Rev. Immunol. 2004 4 583 594 10.1038/nri1412 15286725 208. Walker J.A. McKenzie A.N.J. TH2 cell development and function Nat. Rev. Immunol. 2018 18 121 133 10.1038/nri.2017.118 29082915 209. Saito A. Okazaki H. Sugawara I. Yamamoto K. Takizawa H. Potential action of IL-4 and IL-13 as fibrogenic factors on lung fibroblasts in vitro Int. Arch. Allergy Immunol. 2003 132 168 176 10.1159/000073718 14600429 210. Keane M.P. Belperio J.A. Burdick M.D. Strieter R.M. IL-12 attenuates bleomycin-induced pulmonary fibrosis Am. J. Physiol. Lung Cell. Mol. Physiol. 2001 281 L92 L97 10.1152/ajplung.2001.281.1.L92 11404251 211. Rottoli P. Magi B. Perari M.G. Liberatori S. Nikiforakis N. Bargagli E. Cianti R. Bini L. Pallini V. Cytokine profile and proteome analysis in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systematic sclerosis and idiopathic pulmonary fibrosis Proteomics 2005 5 1423 1430 10.1002/pmic.200301007 15761959 212. Moore M.W. Herzog E.L. Regulatory T Cells in Idiopathic Pulmonary Fibrosis: Too Much of a Good Thing? Am. J. Pathol. 2016 186 1978 1981 10.1016/j.ajpath.2016.06.002 27344432 213. Cheresh P. Kim S.J. Tulasiram S. Kamp D.W. Oxidative stress and pulmonary fibrosis Biochim. Biophys. Acta Mol. Basis Dis. 2013 1832 1028 1040 10.1016/j.bbadis.2012.11.021 214. Richter K. Kietzmann T. Reactive oxygen species and fibrosis: Further evidence of a significant liaison Cell Tissue Res. 2016 365 591 605 10.1007/s00441-016-2445-3 27345301 215. Yue X. Shan B. Lasky J.A. TGF-β: Titan of Lung Fibrogenesis Curr. Enzym. Inhib. 2010 6 1 20 10.2174/157340810791233033 216. Liu R.M. Desai L.P. Reciprocal regulation of TGF-β and reactive oxygen species: A perverse cycle for fibrosis Redox Biol. 2015 6 565 577 10.1016/j.redox.2015.09.009 26496488 217. Kim Y.M. Cho M. Activation of NADPH oxidase subunit NCF4 induces ROS-mediated EMT signaling in HeLa cells Cell. Signal. 2014 26 784 796 10.1016/j.cellsig.2013.12.005 24378533 218. Amara N. Goven D. Prost F. Muloway R. Crestani B. Boczkowski J. NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFβ1-induced fibroblast differentiation into myofibroblasts Thorax 2010 65 733 738 10.1136/thx.2009.113456 20685750 219. Hecker L. Vittal R. Jones T. Jagirdar R. Luckhardt T.R. Horowitz J.C. Pennathur S. Martinez F.J. Thannickal V.J. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury Nat. Med. 2009 15 1077 1081 10.1038/nm.2005 19701206 220. Sturrock A. Cahill B. Norman K. Huecksteadt T.P. Hill K. Sanders K. Karwande S.V. Stringham J.C. Bull D.A. Gleich M. Transforming growth factor-β1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells Am. J. Physiol. Lung Cell. Mol. Physiol. 2006 290 L661 L673 10.1152/ajplung.00269.2005 16227320 221. Waghray M. Cui Z. Horowitz J.C. Subramanian I.M. Martinez F.J. Toews G.B. Thannickal V.J. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts FASEB J. 2005 19 1 16 10.1096/fj.04-2882fje 15629889 222. Koli K. Myllärniemi M. Keski-Oja J. Kinnula V.L. Transforming growth factor-β activation in the lung: Focus on fibrosis and reactive oxygen species Antioxid. Redox Signal. 2008 10 333 342 10.1089/ars.2007.1914 17961070 223. Herrera B. Murillo M.M. Álvarez-Barrientos A. Beltrán J. Fernández M. Fabregat I. Source of early reactive oxygen species in the apoptosis induced by transforming growth factor-β in fetal rat hepatocytes Free Radic. Biol. Med. 2004 36 16 26 10.1016/j.freeradbiomed.2003.09.020 14732287 224. Fois A.G. Paliogiannis P. Sotgia S. Mangoni A.A. Zinellu E. Pirina P. Carru C. Zinellu A. Evaluation of oxidative stress biomarkers in idiopathic pulmonary fibrosis and therapeutic applications: A systematic review Respir. Res. 2018 19 51 10.1186/s12931-018-0754-7 29587761 225. Muramatsu Y. Sugino K. Ishida F. Tatebe J. Morita T. Homma S. Effect of inhaled N-acetylcysteine monotherapy on lung function and redox balance in idiopathic pulmonary fibrosis Respir. Investig. 2016 54 170 178 10.1016/j.resinv.2015.11.004 226. Bowler R.P. Nicks M. Warnick K. Crapo J.D. Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosis Am. J. Physiol. Lung Cell. Mol. Physiol. 2002 282 L719 L726 10.1152/ajplung.00058.2001 11880297 227. Fattman C.L. Chang L.Y. Termin T.A. Petersen L. Enghild J.J. Oury T.D. Enhanced bleomycin-induced pulmonary damage in mice lacking extracellular superoxide dismutase Free Radic. Biol. Med. 2003 35 763 771 10.1016/S0891-5849(03)00402-7 14583340 228. Zelko I.N. Zhu J. Roman J. Role of SOD3 in silica-related lung fibrosis and pulmonary vascular remodeling Respir. Res. 2018 19 221 10.1186/s12931-018-0933-6 30453980 229. Mouradian G.C. Gaurav R. Pugliese S. El Kasmi K. Hartman B. Hernandez-Lagunas L. Stenmark K.R. Bowler R.P. Nozik-Grayck E. Superoxide dismutase 3 R213G single-nucleotide polymorphism blocks murine bleomycin-induced fibrosis and promotes resolution of inflammation Am. J. Respir. Cell Mol. Biol. 2017 56 362 371 10.1165/rcmb.2016-0153OC 27805412 230. Kinnula V.L. Hodgson U.A. Lakari E.K. Tan R.J. Sormunen R.T. Soini Y.M. Kakko S.J. Laitinen T.H. Oury T.D. Pääkkö P.K. Extracellular superoxide dismutase has a highly specific localization in idiopathic pulmonary fibrosis/usual interstitial pneumonia Histopathology 2006 49 66 74 10.1111/j.1365-2559.2006.02470.x 16842247 231. Tiitto L. Kaarteenaho-Wiik R. Sormunen R. Holmgren A. Pääkkö P. Soini Y. Kinnula V.L. Expression of the thioredoxin system in interstitial lung disease J. Pathol. 2003 201 363 370 10.1002/path.1435 14595747 232. Iwata Y. Okamoto M. Hoshino T. Kitasato Y. Sakazaki Y. Tajiri M. Matsunaga K. Azuma K. Kawayama T. Kinoshita T. Elevated levels of thioredoxin 1 in the lungs and sera of idiopathic pulmonary fibrosis, non-specific interstitial pneumonia and cryptogenic organizing pneumonia Intern. Med. 2010 49 2393 2400 10.2169/internalmedicine.49.4049 21088339 233. Richeldi L. Davies H.R.H.R. Spagnolo P. Luppi F. Corticosteroids for idiopathic pulmonary fibrosis Cochrane Database Syst. Rev. 2003 CD002880 10.1002/14651858.CD002880 12917934 234. Martinez F.J. De Andrade J.A. Anstrom K.J. King T.E. Raghu G. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis N. Engl. J. Med. 2014 370 2093 2101 24836309 235. Raghu G. Anstrom K.J. King T.E. Lasky J.A. Martinez F.J. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis N. Engl. J. Med. 2012 366 1968 1977 22607134 236. Richeldi L. Du Bois R.M. Raghu G. Azuma A. Brown K.K. Costabel U. Cottin V. Flaherty K.R. Hansell D.M. Inoue Y. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis N. Engl. J. Med. 2014 370 2071 2082 10.1056/NEJMoa1402584 24836310 237. King T.E. Bradford W.Z. Castro-Bernardini S. Fagan E.A. Glaspole I. Glassberg M.K. Gorina E. Hopkins P.M. Kardatzke D. Lancaster L. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis N. Engl. J. Med. 2014 370 2083 2092 10.1056/NEJMoa1402582 24836312 238. Yoon H.Y. Park S. Kim D.S. Song J.W. Efficacy and safety of nintedanib in advanced idiopathic pulmonary fibrosis Respir. Res. 2018 19 203 10.1186/s12931-018-0907-8 30340638 239. Kistler K.D. Nalysnyk L. Rotella P. Esser D. Lung transplantation in idiopathic pulmonary fibrosis: A systematic review of the literature BMC Pulm. Med. 2014 14 139 10.1186/1471-2466-14-139 25127540 240. Heukels P. Moor C.C. von der Thüsen J.H. Wijsenbeek M.S. Kool M. Inflammation and immunity in IPF pathogenesis and treatment Respir. Med. 2019 147 79 91 10.1016/j.rmed.2018.12.015 30704705 241. Vianello A. Arcaro G. Molena B. Turato C. Braccioni F. Paladini L. Vio S. Ferrarese S. Peditto P. Gallan F. High-flow nasal cannula oxygen therapy to treat acute respiratory failure in patients with acute exacerbation of idiopathic pulmonary fibrosis Ther. Adv. Respir. Dis. 2019 13 1753466619847130 10.1177/1753466619847130 31170875 242. Galli F. Battistoni A. Gambari R. Pompella A. Bragonzi A. Pilolli F. Iuliano L. Piroddi M. Dechecchi M.C. Cabrini G. Oxidative stress and antioxidant therapy in cystic fibrosis Biochim. Biophys. Acta Mol. Basis Dis. 2012 1822 690 713 10.1016/j.bbadis.2011.12.012 243. Chatterjee S. Oxidative Stress, Inflammation, and Disease Oxidative Stress and Biomaterials Elsevier Amsterdam, The Netherlands 2016 35 58 9780128032701 244. Koch C. Hoiby N. Pathogenesis of cystic fibrosis Lancet 1993 341 1065 1069 10.1016/0140-6736(93)92422-P 7682274 245. Cantin A.M. Hartl D. Konstan M.W. Chmiel J.F. Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy J. Cyst. Fibros. 2015 14 419 430 10.1016/j.jcf.2015.03.003 25814049 246. Parkins M.D. Somayaji R. Waters V.J. Epidemiology, Biology, and Impact of Clonal Pseudomonas aeruginosa Infections in Cystic Fibrosis Clin. Microbiol. Rev. 2018 31 e00019-18 10.1128/CMR.00019-18 30158299 247. Huang Y.J. LiPuma J.J. The Microbiome in Cystic Fibrosis Clin. Chest Med. 2016 37 59 67 10.1016/j.ccm.2015.10.003 26857768 248. Turkovic L. Caudri D. Rosenow T. Hall G. Stick S. Presence of mucus plugging is predictive of long term lung function in children with cystic fibrosis Eur. Respir. J. 2017 50 OA4401 249. Rieber N. Hector A. Carevic M. Hartl D. Current concepts of immune dysregulation in cystic fibrosis Int. J. Biochem. Cell Biol. 2014 52 108 112 10.1016/j.biocel.2014.01.017 24495876 250. Nichols D.P. Chmiel J.F. Inflammation and its genesis in cystic fibrosis Pediatr. Pulmonol. 2015 50 S39 S56 10.1002/ppul.23242 26335954 251. Sarr D. Tóth E. Gingerich A. Rada B. Antimicrobial actions of dual oxidases and lactoperoxidase J. Microbiol. 2018 56 373 386 10.1007/s12275-018-7545-1 29858825 252. Rada B. Leto T. Oxidative innate immune defenses by Nox/Duox Family NADPH oxidases Contrib. Microbiol. 2008 15 164 187 18511861 253. Moreau-Marquis S. Coutermarsh B. Stanton B.A. Combination of hypothiocyanite and lactoferrin (ALX-109) enhances the ability of tobramycin and aztreonam to eliminate Pseudomonas aeruginosa biofilms growing on cystic fibrosis airway epithelial cells J. Antimicrob. Chemother. 2015 70 160 166 10.1093/jac/dku357 25213272 254. El-Fakharany E.M. Uversky V.N. Redwan E.M. Comparative Analysis of the Antiviral Activity of Camel, Bovine, and Human Lactoperoxidases Against Herpes Simplex Virus Type 1 Appl. Biochem. Biotechnol. 2017 182 294 310 10.1007/s12010-016-2327-x 27854033 255. Moskwa P. Lorentzen D. Excoffon K.J.D.A. Zabner J. McCray P.B. Nauseef W.M. Dupuy C. Bánfi B. A novel host defense system of airways is defective in cystic fibrosis Am. J. Respir. Crit. Care Med. 2007 175 174 183 10.1164/rccm.200607-1029OC 17082494 256. de Winter-de Groot K.M. van der Ent C.K. Nitric oxide in cystic fibrosis J. Cyst. Fibros. 2005 4 25 29 10.1016/j.jcf.2005.05.008 15982933 257. Grasemann H. Michler E. Wallot M. Ratjen F. Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis Pediatr. Pulmonol. 1997 24 173 177 10.1002/(SICI)1099-0496(199709)24:3<173::AID-PPUL2>3.0.CO;2-O 9330413 258. Causer A.J. Shute J.K. Cummings M.H. Shepherd A.I. Gruet M. Costello J.T. Bailey S. Lindley M. Pearson C. Connett G. Circulating biomarkers of antioxidant status and oxidative stress in people with cystic fibrosis: A systematic review and meta-analysis Redox Biol. 2020 101436 10.1016/j.redox.2020.101436 32044291 259. Fomenko D.E. Koc A. Agisheva N. Jacobsen M. Kaya A. Malinouski M. Rutherford J.C. Siu K.L. Jin D.Y. Winge D.R. Thiol peroxidases mediate specific genome-wide regulation of gene expression in response to hydrogen peroxide Proc. Natl. Acad. Sci. USA 2011 108 2729 2734 10.1073/pnas.1010721108 21282621 260. Rahman I. Antioxidant therapies in COPD Int. J. Chron. Obstruct. Pulmon. Dis. 2006 1 15 29 10.2147/copd.2006.1.1.15 18046899 261. Zhang Z. Leir S.H. Harris A. Oxidative stress regulates CFTR gene expression in human airway epithelial cells through a distal antioxidant response element Am. J. Respir. Cell Mol. Biol. 2015 52 387 396 10.1165/rcmb.2014-0263OC 25259561 262. Chen J. Kinter M. Shank S. Cotton C. Kelley T.J. Ziady A.G. Dysfunction of Nrf-2 in CF epithelia leads to excess intracellular H2O2 and inflammatory cytokine production PLoS ONE 2008 3 e3367 10.1371/journal.pone.0003367 18846238 263. Hudson V.M. Rethinking cystic fibrosis pathology: The critical role of abnormal reduced glutathione (GSH) transport caused by CFTR mutation Free Radic. Biol. Med. 2001 30 1440 1461 10.1016/S0891-5849(01)00530-5 11390189 264. Ghezzi P. Role of glutathione in immunity and inflammation in the lung Int. J. Gen. Med. 2011 4 105 113 10.2147/IJGM.S15618 21403800 265. de Bari L. Favia M. Bobba A. Lassandro R. Guerra L. Atlante A. Aberrant GSH reductase and NOX activities concur with defective CFTR to pro-oxidative imbalance in cystic fibrosis airways J. Bioenerg. Biomembr. 2018 50 117 129 10.1007/s10863-018-9748-x 29524019 266. Kettle A.J. Turner R. Gangell C.L. Harwood D.T. Khalilova I.S. Chapman A.L. Winterbourn C.C. Sly P.D. Oxidation contributes to low glutathione in the airways of children with cystic fibrosis Eur. Respir. J. 2014 44 122 129 10.1183/09031936.00170213 24659542 267. Sathe M.N. Patel A.S. Update in pediatrics: Focus on fat-soluble vitamins Nutr. Clin. Pract. 2010 25 340 346 10.1177/0884533610374198 20702838 268. Traber M.G. The ABCs of vitamin E and β-carotene absorption Am. J. Clin. Nutr. 2004 80 3 4 10.1093/ajcn/80.1.3 15213020 269. Back E.I. Frindt C. Nohr D. Frank J. Ziebach R. Stern M. Ranke M. Biesalski H.K. Antioxidant deficiency in cystic fibrosis: When is the right time to take action? Am. J. Clin. Nutr. 2004 80 374 384 10.1093/ajcn/80.2.374 15277158 270. Wood Z.A. Schröder E. Harris J.R. Poole L.B. Structure, mechanism and regulation of peroxiredoxins Trends Biochem. Sci. 2003 28 32 40 10.1016/S0968-0004(02)00003-8 12517450 271. Iuliano L. Monticolo R. Straface G. Zullo S. Galli F. Boaz M. Quattrucci S. Association of cholesterol oxidation and abnormalities in fatty acid metabolism in cystic fibrosis Am. J. Clin. Nutr. 2009 90 477 484 10.3945/ajcn.2009.27757 19587087 272. Gunasekara L. Al-Saiedy M. Green F. Pratt R. Bjornson C. Yang A. Michael Schoel W. Mitchell I. Brindle M. Montgomery M. Pulmonary surfactant dysfunction in pediatric cystic fibrosis: Mechanisms and reversal with a lipid-sequestering drug J. Cyst. Fibros. 2017 16 565 572 10.1016/j.jcf.2017.04.015 28599957 273. Cheer S.M. Waugh J. Noble S. Inhaled Tobramycin (TOBI® ): A Review of its Use in the Management of Pseudomonas aeruginosa Infections in Patients with Cystic Fibrosis Drugs 2003 63 2501 2520 10.2165/00003495-200363220-00015 14609360 274. Chmiel J.F. Konstan M.W. Elborn J.S. Antibiotic and anti-inflammatory therapies for cystic fibrosis Cold Spring Harb. Perspect. Med. 2013 3 a009779 10.1101/cshperspect.a009779 23880054 275. Nichols D.P. Durmowicz A.G. Field A. Flume P.A. VanDevanter D.R. Mayer-Hamblett N. Developing inhaled antibiotics in cystic fibrosis: Current challenges and opportunities Ann. Am. Thorac. Soc. 2019 16 534 539 10.1513/AnnalsATS.201812-863OT 30658043 276. Moss R.B. Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis Chest 2002 121 55 63 10.1378/chest.121.1.55 11796432 277. Konstan M.W. Flume P.A. Kappler M. Chiron R. Higgins M. Brockhaus F. Zhang J. Angyalosi G. He E. Geller D.E. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial J. Cyst. Fibros. 2011 10 54 61 10.1016/j.jcf.2010.10.003 21075062 278. Hengzhuang W. Green K. Pressler T. Skov M. Katzenstein T.L. Wu X. Høiby N. Optimization of colistin dosing regimen for cystic fibrosis patients with chronic Pseudomonas aeruginosa biofilm lung infections Pediatr. Pulmonol. 2019 54 575 580 10.1002/ppul.24269 30803159 279. Konstan M.W. Ibuprofen therapy for cystic fibrosis lung disease: Revisited Curr. Opin. Pulm. Med. 2008 14 567 573 10.1097/MCP.0b013e32831311e8 18812834 280. Lands L.C. Stanojevic S. Oral non-steroidal anti-inflammatory drug therapy for cystic fibrosis Cochrane Database Syst. Rev. 1999 CD001505 10.1002/14651858.CD001505 281. Köhler E. Sollich V. Schuster-Wonka R. Jorch G. Lung deposition after electronically breath-controlled inhalation and manually triggered conventional inhalation in cystic fibrosis patients J. Aerosol Med. Depos. Clear. Eff. Lung 2005 18 386 395 10.1089/jam.2005.18.386 282. Salvatore D. D’Andria M. Effects of salmeterol on arterial oxyhemoglobin saturations in patients with cystic fibrosis Pediatr. Pulmonol. 2002 34 11 15 10.1002/ppul.10117 12112791 283. Robinson M. Regnis J.A. Bailey D.L. King M. Bautovich G.J. Bye P.T.P. Effect of hypertonic saline, amiloride, and cough on mucociliary clearance in patients with cystic fibrosis Am. J. Respir. Crit. Care Med. 1996 153 1503 1509 10.1164/ajrccm.153.5.8630593 8630593 284. Quan J.M. Tiddens H.A.W.M. Sy J.P. McKenzie S.G. Montgomery M.D. Robinson P.J. Wohl M.E.B. Konstan M.W. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities J. Pediatr. 2001 139 813 820 10.1067/mpd.2001.118570 11743506 285. Yang C. Montgomery M. Dornase alfa for cystic fibrosis Cochrane Database Syst. Rev. 2018 2018 CD001127 10.1002/14651858.CD001127.pub4 286. Shak S. Capon D.J. Hellmiss R. Marsters S.A. Baker C.L. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum Proc. Natl. Acad. Sci. USA 1990 87 9188 9192 10.1073/pnas.87.23.9188 2251263 287. Aitken M.L. Burke W. McDonald G. Shak S. Montgomery A.B. Smith A. Recombinant human DNase inhalation in normal subjects and patients with cystic fibrosis. A phase 1 study JAMA 1992 267 1947 1951 10.1001/jama.1992.03480140073036 1548827 288. Hubbard R.C. Mcelvaney N.G. Birrer P. Robinson W.W. Jolley C. Crystal R.G. Shak S. Wu M. Chernick M.S. A preliminary study of aerosolized recombinant human deoxyribonuclease i in the treatment of cystic fibrosis N. Engl. J. Med. 1992 326 812 815 10.1056/NEJM199203193261207 1538726 289. Radtke T. Nevitt S.J. Hebestreit H. Kriemler S. Physical exercise training for cystic fibrosis Cochrane Database Syst. Rev. 2017 2017 CD002768 10.1002/14651858.CD002768.pub4 29090734 290. Morrison L. Milroy S. Oscillating devices for airway clearance in people with cystic fibrosis Cochrane Database Syst. Rev. 2020 2020 CD006842 291. Shaw T.D. McAuley D.F. O’Kane C.M. Emerging drugs for treating the acute respiratory distress syndrome Expert Opin. Emerg. Drugs 2019 24 29 41 10.1080/14728214.2019.1591369 30841764 292. Villar J. Ferrando C. Martínez D. Ambrós A. Muñoz T. Soler J.A. Aguilar G. Alba F. González-Higueras E. Conesa L.A. Dexamethasone treatment for the acute respiratory distress syndrome: A multicentre, randomised controlled trial Lancet Respir. Med. 2020 8 267 276 10.1016/S2213-2600(19)30417-5 32043986 293. Villar J. Belda J. Añón J.M. Blanco J. Pérez-Méndez L. Ferrando C. Martínez D. Soler J.A. Ambrós A. Muñoz T. Evaluating the efficacy of dexamethasone in the treatment of patients with persistent acute respiratory distress syndrome: Study protocol for a randomized controlled trial Trials 2016 17 342 10.1186/s13063-016-1456-4 27449641 294. Festic E. Carr G.E. Cartin-Ceba R. Hinds R.F. Banner-Goodspeed V. Bansal V. Asuni A.T. Talmor D. Rajagopalan G. Frank R.D. Randomized clinical trial of a combination of an inhaled corticosteroid and beta agonist in patients at risk of developing the acute respiratory distress syndrome Crit. Care Med. 2017 45 798 805 10.1097/CCM.0000000000002284 28240689 295. Matthay M.A. McAuley D.F. Ware L.B. Clinical trials in acute respiratory distress syndrome: Challenges and opportunities Lancet Respir. Med. 2017 5 524 534 10.1016/S2213-2600(17)30188-1 28664851 296. NCT03096314 Vitamin D to Improve Outcomes by Leveraging Early Treatment 2017 Available online: https://clinicaltrials.gov/show/NCT03096314 (accessed on 2 May 2020) 297. Parekh D. Dancer R.C.A. Scott A. D’Souza V.K. Howells P.A. Mahida R.Y. Tang J.C.Y. Cooper M.S. Fraser W.D. Tan L.C. Vitamin D to Prevent Lung Injury Following Esophagectomy-A Randomized, Placebo-Controlled Trial Crit. Care Med. 2018 46 e1128 e1135 10.1097/CCM.0000000000003405 30222631 298. Ginde A.A. Brower R.G. Caterino J.M. Finck L. Banner-Goodspeed V.M. Grissom C.K. Hayden D. Hough C.L. Hyzy R.C. Khan A. Early high-dose Vitamin D3 for critically ill, Vitamin D–deficient patients N. Engl. J. Med. 2019 381 2529 2540 31826336 299. Toner P. McAuley D.F. Shyamsundar M. Aspirin as a potential treatment in sepsis or acute respiratory distress syndrome Crit. Care 2015 19 374 10.1186/s13054-015-1091-6 26494395 300. Harr J.N. Moore E.E. Johnson J. Chin T.L. Wohlauer M.V. Maier R. Cuschieri J. Sperry J. Banerjee A. Silliman C.C. Antiplatelet therapy is associated with decreased transfusion-associated risk of lung dysfunction, multiple organ failure, and mortality in trauma patients Crit. Care Med. 2013 41 399 404 10.1097/CCM.0b013e31826ab38b 23263579 301. Hamid U. Krasnodembskaya A. Fitzgerald M. Shyamsundar M. Kissenpfennig A. Scott C. Lefrancais E. Looney M.R. Verghis R. Scott J. Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS Thorax 2017 72 971 980 10.1136/thoraxjnl-2016-208571 28082531 302. Matthay M.A. Calfee C.S. Zhuo H. Thompson B.T. Wilson J.G. Levitt J.E. Rogers A.J. Gotts J.E. Wiener-Kronish J.P. Bajwa E.K. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): A randomised phase 2a safety trial Lancet Respir. Med. 2019 7 154 162 10.1016/S2213-2600(18)30418-1 30455077 303. Fisher B.J. Kraskauskas D. Martin E.J. Farkas D. Wegelin J.A. Brophy D. Ward K.R. Voelkel N.F. Fowler A.A. Natarajan R. Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid Am. J. Physiol. Lung Cell. Mol. Physiol. 2012 303 L20 L32 10.1152/ajplung.00300.2011 22523283 304. NCT02106975 Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury—Full Text View—ClinicalTrials.gov 2019 Available online: https://clinicaltrials.gov/show/NCT02106975 (accessed on 20 September 2020) 305. Fowler A.A. Truwit J.D. Hite R.D. Morris P.E. Dewilde C. Priday A. Fisher B. Thacker L.R. Natarajan R. Brophy D.F. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients with Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial JAMA J. Am. Med. Assoc. 2019 322 1261 1270 10.1001/jama.2019.11825 306. Dixon B. Schultz M.J. Smith R. Fink J.B. Santamaria J.D. Campbell D.J. Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: A randomized controlled trial Crit. Care 2010 14 R180 10.1186/cc9286 20937093 307. ACTRN12612000418875 A Multi-Centre Randomised, Placebo Controlled Trial of Nebulised Heparin in Patients with or at Risk of Developing Acute Respiratory Distress Syndrome, to Determine if Nebulised Heparin Improves Long Term Physical Function. Australian New Zealand Clinical Trials Registry 2012 Available online: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362354 (accessed on 25 September 2020) 308. Morris P.E. Steingrub J.S. Huang B.Y. Tang S. Liu P.M. Rhode P.R. Wong H.C. A phase I study evaluating the pharmacokinetics, safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung injury or acute respiratory distress syndrome BMC Pulm. Med. 2012 12 5 10.1186/1471-2466-12-5 22340260 309. NCT00879606 Anti-TF Antibody (ALT-836) to Treat Septic Patients With Acute Lung Injury or Acute Respiratory Distress Syndrome—Full Text View—ClinicalTrials.gov 2015 Available online: https://clinicaltrials.gov/show/NCT00879606 (accessed on 2 May 2020) 310. Denham W. Yang J. Norman J. Wang H. Botchkina G. Tracey K.J. Inhibition of p38 mitogen activate kinase attenuates the severity of pancreatitis-induced adult respiratory distress syndrome Crit. Care Med. 2000 28 2567 2572 10.1097/00003246-200007000-00064 10921596 311. Christie J.D. Vaslef S. Chang P.K. May A.K. Gunn S.R. Yang S. Hardes K. Kahl L. Powley W.M. Lipson D.A. A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome Crit. Care Med. 2015 43 1859 1869 10.1097/CCM.0000000000001132 26102252 312. Tagami T. Tosa R. Omura M. Fukushima H. Kaneko T. Endo T. Rinka H. Murai A. Yamaguchi J. Yoshikawa K. Effect of a selective neutrophil elastase inhibitor on mortality and ventilator-free days in patients with increased extravascular lung water: A post hoc analysis of the PiCCO Pulmonary Edema Study J. Intensive Care 2014 2 67 10.1186/s40560-014-0067-y 25705423 313. Kido T. Muramatsu K. Yatera K. Asakawa T. Otsubo H. Kubo T. Fujino Y. Matsuda S. Mayumi T. Mukae H. Efficacy of early sivelestat administration on acute lung injury and acute respiratory distress syndrome Respirology 2017 22 708 713 10.1111/resp.12969 27990710 314. Pu S. Wang D. Liu D. Zhao Y. Qi D. He J. Zhou G. Effect of sivelestat sodium in patients with acute lung injury or acute respiratory distress syndrome: A meta-analysis of randomized controlled trials BMC Pulm. Med. 2017 17 148 10.1186/s12890-017-0498-z 29162066 315. Cao Y.Z. Tu Y.Y. Chen X. Wang B.L. Zhong Y.X. Liu M.H. Protective effect of Ulinastatin against murine models of sepsis: Inhibition of TNF-α and IL-6 and augmentation of IL-10 and IL-13 Exp. Toxicol. Pathol. 2012 64 543 547 10.1016/j.etp.2010.11.011 21159497 316. Leng Y.-X. Ulinastatin for acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis World J. Crit. Care Med. 2014 3 34 10.5492/wjccm.v3.i1.34 24834400 317. NCT02895191 The Safety and Dose Response Relationship of Ulinastatin for Acute Respiratory Distress Syndrome(ARDS)—Full Text View—ClinicalTrials.gov 2018 Available online: https://clinicaltrials.gov/show/NCT02895191 (accessed on 2 May 2020) 318. Paine R. Standiford T.J. Dechert R.E. Moss M. Martin G.S. Rosenberg A.L. Thannickal V.J. Burnham E.L. Brown M.B. Hyzy R.C. A randomized Trial of recombinant human granulocyte-macrophage colony stimulating factor for Patients with acute lung injury Crit. Care Med. 2012 40 90 97 10.1097/CCM.0b013e31822d7bf0 21926600 319. Frevert C.W. Matute-Bello G. Skerrett S.J. Goodman R.B. Kajikawa O. Sittipunt C. Martin T.R. Effect of CD14 Blockade in Rabbits with Escherichia coli Pneumonia and Sepsis J. Immunol. 2000 164 5439 5445 10.4049/jimmunol.164.10.5439 10799910 320. NCT03017547 A Phase 2 Study of IC14 in Acute Respiratory Distress Syndrome—Full Text View—ClinicalTrials.gov 2019 Available online: https://clinicaltrials.gov/show/NCT03017547 (accessed on 2 May 2020) 321. Fuller B.M. Mohr N.M. Skrupky L. Fowler S. Kollef M.H. Carpenter C.R. The use of inhaled prostaglandins in patients with ARDS: A systematic review and meta-analysis Chest 2015 147 1510 1522 10.1378/chest.14-3161 25742022 322. Bosmann M. Grailer J.J. Ruemmler R. Russkamp N.F. Zetoune F.S. Sarma J.V. Standiford T.J. Ward P.A. Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury FASEB J. 2013 27 5010 5021 10.1096/fj.13-236380 23982144 323. Wildhagen K.C.A.A. De Frutos P.G. Reutelingsperger C.P. Schrijver R. Aresté C. Ortega-Gómez A. Deckers N.M. Hemker H.C. Soehnlein O. Nicolaes G.A.F. Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis Blood 2014 123 1098 1101 10.1182/blood-2013-07-514984 24264231 324. Kalliolias G.D. Liossis S.N.C. The future of the IL-1 receptor antagonist anakinra: From rheumatoid arthritis to adult-onset still’s disease and systemic-onset juvenile idiopathic arthritis Expert Opin. Investig. Drugs 2008 17 349 359 10.1517/13543784.17.3.349 18321234 325. Liu D. Lon H.K. DuBois D.C. Almon R.R. Jusko W.J. Population pharmacokinetic-pharmacodynamic-disease progression model for effects of anakinra in Lewis rats with collagen-induced arthritis J. Pharmacokinet. Pharmacodyn. 2011 38 769 786 10.1007/s10928-011-9219-z 22002845 326. Patel V.J. Biswas Roy S. Mehta H.J. Joo M. Sadikot R.T. Alternative and Natural Therapies for Acute Lung Injury and Acute Respiratory Distress Syndrome Biomed Res. Int. 2018 2018 2476824 10.1155/2018/2476824 29862257 327. Wechsler M.E. Current and emerging biologic therapies for asthma and copd Respir. Care 2018 63 699 707 10.4187/respcare.06322 29794205 328. Calhoun K.H. Asthma treatments: New and emerging therapies Int. Forum Allergy Rhinol. 2015 5 S76 S81 10.1002/alr.21611 26335840 329. Durham A.L. Caramori G. Chung K.F. Adcock I.M. Targeted anti-inflammatory therapeutics in asthma and chronic obstructive lung disease Transl. Res. 2016 167 192 203 10.1016/j.trsl.2015.08.004 26334389 330. Tashkin D.P. Wechsler M.E. Role of eosinophils in airway inflammation of chronic obstructive pulmonary disease Int. J. COPD 2018 13 335 349 10.2147/COPD.S152291 331. Corren J. Casale T. Deniz Y. Ashby M. Omalizumab, a recombinant humanized anti-IgE antibody, reduces asthma-related emergency room visits and hospitalizations in patients with allergic asthma J. Allergy Clin. Immunol. 2003 111 87 90 10.1067/mai.2003.49 12532101 332. Cowan D.C. Taylor D.R. Peterson L.E. Cowan J.O. Palmay R. Williamson A. Hammel J. Erzurum S.C. Hazen S.L. Comhair S.A.A. Biomarker-based asthma phenotypes of corticosteroid response J. Allergy Clin. Immunol. 2015 135 877 883.e1 10.1016/j.jaci.2014.10.026 25488689 333. Fajt M.L. Wenzel S.E. Biologic therapy in asthma: Entering the new age of personalized medicine J. Asthma 2014 51 669 676 10.3109/02770903.2014.910221 24712500 334. Apter A.J. Advances in adult asthma diagnosis and treatment in 2014 J. Allergy Clin. Immunol. 2015 135 46 53 10.1016/j.jaci.2014.10.050 25567042 335. Ortega H.G. Liu M.C. Pavord I.D. Brusselle G.G. FitzGerald J.M. Chetta A. Humbert M. Katz L.E. Keene O.N. Yancey S.W. Mepolizumab treatment in patients with severe eosinophilic asthma N. Engl. J. Med. 2014 371 1198 1207 10.1056/NEJMoa1403290 25199059 336. Albers F.C. Hozawa S. Bratton D.J. Yancey S.W. Prazma C.M. Humbert M. Liu M.C. Update: Mepolizumab treatment in patients with severe eosinophilic asthma and prior omalizumab use Allergy Eur. J. Allergy Clin. Immunol. 2020 75 942 946 10.1111/all.14048 31520471 337. Flood-Page P.T. Menzies-Gow A.N. Kay A.B. Robinson D.S. Eosinophil’s role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway Am. J. Respir. Crit. Care Med. 2003 167 199 204 10.1164/rccm.200208-789OC 12406833 338. Haldar P. Brightling C.E. Singapuri A. Hargadon B. Gupta S. Monteiro W. Bradding P. Green R.H. Wardlaw A.J. Ortega H. Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: A 12-month follow-up analysis J. Allergy Clin. Immunol. 2014 133 921 923 10.1016/j.jaci.2013.11.026 24418480 339. Castro M. Zangrilli J. Wechsler M.E. Bateman E.D. Brusselle G.G. Bardin P. Murphy K. Maspero J.F. O’Brien C. Korn S. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: Results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials Lancet Respir. Med. 2015 3 355 366 10.1016/S2213-2600(15)00042-9 25736990 340. Castro M. King T.S. Kunselman S.J. Cabana M.D. Denlinger L. Holguin F. Kazani S.D. Moore W.C. Moy J. Sorkness C.A. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: The VIDA randomized clinical trial JAMA J. Am. Med. Assoc. 2014 311 2083 2091 10.1001/jama.2014.5052 341. Ibrahim H. O’Sullivan R. Casey D. Murphy J. MacSharry J. Plant B.J. Murphy D.M. The effectiveness of Reslizumab in severe asthma treatment: A real-world experience Respir. Res. 2019 20 289 10.1186/s12931-019-1251-3 31861993 342. Christian Virchow J. McDonald M. Garin M. Korn S. Reslizumab as add-on therapy in patients with refractory asthma BMJ Open Respir. Res. 2020 7 e000494 10.1136/bmjresp-2019-000494 343. Markham A. Benralizumab: First Global Approval Drugs 2018 78 505 511 10.1007/s40265-018-0876-8 29464664 344. Saco T.V. Pepper A.N. Lockey R.F. Benralizumab for the treatment of asthma Expert Rev. Clin. Immunol. 2017 13 405 413 10.1080/1744666X.2017.1316194 28379047 345. Bleecker E.R. FitzGerald J.M. Chanez P. Papi A. Weinstein S.F. Barker P. Sproule S. Gilmartin G. Aurivillius M. Werkström V. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): A randomised, multicentre, placebo-controlled phase 3 trial Lancet 2016 388 2115 2127 10.1016/S0140-6736(16)31324-1 27609408 346. Nair P. Wenzel S. Rabe K.F. Bourdin A. Lugogo N.L. Kuna P. Barker P. Sproule S. Ponnarambil S. Goldman M. Oral glucocorticoid-sparing effect of benralizumab in severe asthma N. Engl. J. Med. 2017 376 2448 2458 10.1056/NEJMoa1703501 28530840 347. Shirley M. Dupilumab: First Global Approval Drugs 2017 77 1115 1121 10.1007/s40265-017-0768-3 28547386 348. Rabe K.F. Nair P. Brusselle G. Maspero J.F. Castro M. Sher L. Zhu H. Hamilton J.D. Swanson B.N. Khan A. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma N. Engl. J. Med. 2018 378 2475 2485 10.1056/NEJMoa1804093 29782224 349. Castro M. Corren J. Pavord I.D. Maspero J. Wenzel S. Rabe K.F. Busse W.W. Ford L. Sher L. FitzGerald J.M. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma N. Engl. J. Med. 2018 378 2486 2496 10.1056/NEJMoa1804092 29782217 350. Hanania N.A. Korenblat P. Chapman K.R. Bateman E.D. Kopecky P. Paggiaro P. Yokoyama A. Olsson J. Gray S. Holweg C.T.J. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): Replicate, phase 3, randomised, double-blind, placebo-controlled trials Lancet Respir. Med. 2016 4 781 796 10.1016/S2213-2600(16)30265-X 27616196 351. Brightling C.E. Chanez P. Leigh R. O’Byrne P.M. Korn S. She D. May R.D. Streicher K. Ranade K. Piper E. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: A randomised, double-blind, placebo-controlled, phase 2b trial Lancet Respir. Med. 2015 3 692 701 10.1016/S2213-2600(15)00197-6 26231288 352. Korenblat P. Kerwin E. Leshchenko I. Yen K. Holweg C.T.J. Anzures-Cabrera J. Martin C. Putnam W.S. Governale L. Olsson J. Efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma not receiving inhaled corticosteroids Respir. Med. 2018 134 143 149 10.1016/j.rmed.2017.12.006 29413502 353. Busse W.W. Brusselle G.G. Korn S. Kuna P. Magnan A. Cohen D. Bowen K. Piechowiak T. Wang M.M. Colice G. Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma Eur. Respir. J. 2019 53 1800948 10.1183/13993003.00948-2018 30442714 354. NCT03927157 Study to Evaluate Tezepelumab in Adults With Severe Uncontrolled Asthma—Full Text View—ClinicalTrials.gov 2020 Available online: https://clinicaltrials.gov/show/NCT03927157 (accessed on 2 May 2020) 355. Marone G. Spadaro G. Braile M. Poto R. Criscuolo G. Pahima H. Loffredo S. Levi-Schaffer F. Varricchi G. Tezepelumab: A novel biological therapy for the treatment of severe uncontrolled asthma Expert Opin. Investig. Drugs 2019 28 931 940 10.1080/13543784.2019.1672657 31549891 356. Ding W. Zou G.L. Zhang W. Lai X.N. Chen H.W. Xiong L.X. Interleukin-33: Its emerging role in allergic diseases Molecules 2018 23 1665 10.3390/molecules23071665 29987222 357. Busse W.W. Holgate S. Kerwin E. Chon Y. Feng J. Lin J. Lin S. Study of Brodalumab, a Human Anti – IL-17 Receptor Monoclonal Antibody, in Moderate to Severe Asthma Am. J. Respir. Crit. Care Med. 2013 188 1294 1302 10.1164/rccm.201212-2318OC 24200404 358. Nair P. Gaga M. Zervas E. Alagha K. Hargreave F.E. O’Byrne P.M. Stryszak P. Gann L. Sadeh J. Chanez P. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: A randomized, placebo-controlled clinical trial Clin. Exp. Allergy 2012 42 1097 1103 10.1111/j.1365-2222.2012.04014.x 22702508 359. NCT00632502 Neutrophilic Asthma Study With Navarixin (MK-7123, SCH 527123) (MK-7123-017)(COMPLETED)—Full Text View—ClinicalTrials.gov 2019 Available online: https://clinicaltrials.gov/show/NCT00632502 (accessed on 2 May 2020) 360. Imaoka H. Campbell H. Babirad I. Watson R.M. Mistry M. Sehmi R. Gauvreau G.M. TPI ASM8 reduces eosinophil progenitors in sputum after allergen challenge Clin. Exp. Allergy 2011 41 1740 1746 10.1111/j.1365-2222.2011.03816.x 21762225 361. Cahill K.N. Katz H.R. Cui J. Lai J. Kazani S. Crosby-Thompson A. Garofalo D. Castro M. Jarjour N. DiMango E. KIT inhibition by imatinib in patients with severe refractory asthma N. Engl. J. Med. 2017 376 1911 1920 10.1056/NEJMoa1613125 28514613 362. Howarth P.H. Babu K.S. Arshad H.S. Lau L. Buckley M. McConnell W. Beckett P. Al Ali M. Chauhan A. Wilson S.J. Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma Thorax 2005 60 1012 1018 10.1136/thx.2005.045260 16166100 363. Oliveri C. Polosa R. Etanercept in chronic severe asthma Thorax 2006 61 640 16807393 364. Holgate S.T. Noonan M. Chanez P. Busse W. Dupont L. Pavord I. Hakulinen A. Paolozzi L. Wajdula J. Zang C. Efficacy and safety of etanercept in moderate-to-severe asthma: A randomised, controlled trial Eur. Respir. J. 2011 37 1352 1359 10.1183/09031936.00063510 21109557 365. Morjaria J.B. Chauhan A.J. Babu K.S. Polosa R. Davies D.E. Holgate S.T. The role of a soluble TNFα receptor fusion protein (etanercept) in corticosteroid refractory asthma: A double blind, randomised, placebo controlled trial Thorax 2008 63 584 591 10.1136/thx.2007.086314 18245148 366. Zhu L.-Y. Ni Z.-H. Luo X.-M. Wang X.-B. Advance of antioxidants in asthma treatment World J. Respirol. 2017 7 17 10.5320/wjr.v7.i1.17 367. Bray T.M. Bettger W.J. The physiological role of zinc as an antioxidant Free Radic. Biol. Med. 1990 8 281 291 10.1016/0891-5849(90)90076-U 2187766 368. Machlin L.J. Bendich A. Free radical tissue damage: Protective role of antioxidant nutrients FASEB J. 1987 1 441 445 10.1096/fasebj.1.6.3315807 3315807 369. Wood L.G. Garg M.L. Smart J.M. Scott H.A. Barker D. Gibson P.G. Manipulating antioxidant intake in asthma: A randomized controlled trial1-3 Am. J. Clin. Nutr. 2012 96 534 543 10.3945/ajcn.111.032623 22854412 370. Kurti S.P. Rosenkranz S.K. Chapes S.K. Teeman C.S. Cull B.J. Emerson S.R. Levitt M.H. Smith J.R. Harms C.A. Does chronic physical activity level modify the airway inflammatory response to an acute bout of exercise in the postprandial period? Appl. Physiol. Nutr. Metab. 2017 42 173 180 10.1139/apnm-2016-0335 28121185 371. Eftekhari P. Hajizadeh S. Reza Raoufy M. Reza Masjedi M. Yang M. Hansbro N. Li J.J. Foster P.S. Preventive effect of N-acetylcysteine in a mouse model of steroid resistant acute exacerbation of asthma EXCLI J. 2013 12 184 192 26417226 372. NCT02605824 Clinical Trial of NAC in Asthma—Full Text View—ClinicalTrials.gov 2019 Available online: https://clinicaltrials.gov/show/NCT02605824 (accessed on 2 May 2020) 373. Sakoda C.P.P. de Toledo A.C. Perini A. Pinheiro N.M. Hiyane M.I. dos Grecco S.S. de Fátima Lopes Calvo Tibério I. Câmara N.O.S. de Arruda Martins M. Lago J.H.G. Sakuranetin reverses vascular peribronchial and lung parenchyma remodeling in a murine model of chronic allergic pulmonary inflammation Acta Histochem. 2016 118 615 624 10.1016/j.acthis.2016.07.001 27425653 374. Toledo A.C. Sakoda C.P.P. Perini A. Pinheiro N.M. Magalhães R.M. Grecco S. Tibério I.F.L.C. Câmara N.O. Martins M.A. Lago J.H.G. Flavonone treatment reverses airway inflammation and remodelling in an asthma murine model Br. J. Pharmacol. 2013 168 1736 1749 10.1111/bph.12062 23170811 375. Cho I.H. Choi Y.J. Gong J.H. Shin D. Kang M.K. Kang Y.H. Astragalin inhibits autophagy-associated airway epithelial fibrosis Respir. Res. 2015 16 51 10.1186/s12931-015-0211-9 25895672 376. Cho I.H. Gong J.H. Kang M.K. Lee E.J. Park J.H.Y. Park S.J. Kang Y.H. Astragalin inhibits airway eotaxin-1 induction and epithelial apoptosis through modulating oxidative stress-responsive MAPK signaling BMC Pulm. Med. 2014 14 122 10.1186/1471-2466-14-122 25069610 377. André D.M. Calixto M.C. Sollon C. Alexandre E.C. Leiria L.O. Tobar N. Anhê G.F. Antunes E. Therapy with resveratrol attenuates obesity-associated allergic airway inflammation in mice Int. Immunopharmacol. 2016 38 298 305 10.1016/j.intimp.2016.06.017 27344038 378. André D.M. Calixto M.C. Sollon C. Alexandre E.C. Tavares E.B.G. Naime A.C.A. Anhê G.F. Antunes E. High-fat diet-induced obesity impairs insulin signaling in lungs of allergen-challenged mice: Improvement by resveratrol Sci. Rep. 2017 7 17296 10.1038/s41598-017-17558-w 29229986 379. Kandhare A.D. Liu Z. Mukherjee A.A. Bodhankar S.L. Therapeutic Potential of Morin in Ovalbumin-induced Allergic Asthma Via Modulation of SUMF2/IL-13 and BLT2/NF-kB Signaling Pathway Curr. Mol. Pharmacol. 2019 12 122 138 10.2174/1874467212666190102105052 30605067 380. Bokhari J. Khan M.R. Evaluation of anti-asthmatic and antioxidant potential of Boerhavia procumbens in toluene diisocyanate (TDI) treated rats J. Ethnopharmacol. 2015 172 377 385 10.1016/j.jep.2015.06.049 26151242 381. Wang L. Xu M.L. Liu J. Wang Y. Hu J.H. Wang M.H. Sonchus asper extract inhibits LPS-induced oxidative stress and pro-inflammatory cytokine production in RAW264.7 macrophages Nutr. Res. Pract. 2015 9 579 585 10.4162/nrp.2015.9.6.579 26634045 382. Ci X. Zhong W. Ren H. Wen Z. Li D. Peng L. Esculentoside a attenuates allergic airway inflammation via activation of the Nrf-2 pathway Int. Arch. Allergy Immunol. 2015 167 280 290 10.1159/000441061 26496193 383. Jang H.Y. Kim S.M. Yuk J.E. Kwon O.K. Oh S.R. Lee H.K. Jeong H. Ahn K.S. Capsicum annuum L. methanolic extract inhibits ovalbumin-induced airway inflammation and oxidative stress in a mouse model of asthma J. Med. Food 2011 14 1144 1151 10.1089/jmf.2011.1609 21875363 384. Sahreen S. Khan M.R. Khan R.A. Alkreathy H.M. Cardioprotective role of leaves extracts of Carissa opaca against CCl 4 induced toxicity in rats BMC Res. Notes 2014 7 224 10.1186/1756-0500-7-224 24716654 385. Bouch S. Harding R. O’Reilly M. Wood L.G. Sozo F. Impact of dietary tomato juice on changes in pulmonary oxidative stress, inflammation and structure induced by neonatal hyperoxia in mice (Mus musculus) PLoS ONE 2016 11 e0159633 10.1371/journal.pone.0159633 27438045 386. Pigati P.A. Righetti R.F. Possa S.S. Romanholo B.S. Rodrigues A.P.D. dos Santos A.S.A. Xisto D.G. Antunes M.A. Prado C.M. Leick E.A. Y-27632 is associated with corticosteroid-potentiated control of pulmonary remodeling and inflammation in guinea pigs with chronic allergic inflammation BMC Pulm. Med. 2015 15 85 10.1186/s12890-015-0073-4 26264367 387. Righetti R.F. da Pigati P.A.S. Possa S.S. Habrum F.C. Xisto D.G. Antunes M.A. Leick E.A. Prado C.M. de Martins M.A. Rocco P.R.M. Effects of Rho-kinase inhibition in lung tissue with chronic inflammation Respir. Physiol. Neurobiol. 2014 192 134 146 10.1016/j.resp.2013.12.012 24373838 388. Aristoteles L.R.C.R.B. Righetti R.F. Pinheiro N.M. Franco R.B. Starling C.M. da Silva J.C.P. Pigati P.A. Caperuto L.C. Prado C.M. Dolhnikoff M. Modulation of the oscillatory mechanics of lung tissue and the oxidative stress response induced by arginase inhibition in a chronic allergic inflammation model BMC Pulm. Med. 2013 13 1 13 10.1186/1471-2466-13-52 23305075 389. Campos D. Ravagnani F.G. Gurgueira S.A. Vercesi A.E. Teixeira S.A. Costa S.K.P. Muscará M.N. Ferreira H.H.A. Increased glutathione levels contribute to the beneficial effects of hydrogen sulfide and inducible nitric oxide inhibition in allergic lung inflammation Int. Immunopharmacol. 2016 39 57 62 10.1016/j.intimp.2016.07.009 27424079 390. Lucarini L. Pini A. Gerace E. Pellicciari R. Masini E. Moroni F. Poly(ADP-ribose) polymerase inhibition with HYDAMTIQ reduces allergen-induced asthma-like reaction, bronchial hyper-reactivity and airway remodelling J. Cell. Mol. Med. 2014 18 468 479 10.1111/jcmm.12197 24444146 391. Dhawale V.S. Amara V.R. Karpe P.A. Malek V. Patel D. Tikoo K. Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model Toxicol. Appl. Pharmacol. 2016 306 17 26 10.1016/j.taap.2016.06.026 27343405 392. Ho C.Y. Lu C.C. Weng C.J. Yen G.C. Protective Effects of Diallyl Sulfide on Ovalbumin-Induced Pulmonary Inflammation of Allergic Asthma Mice by MicroRNA-144, -34a, and -34b/c-Modulated Nrf2 Activation J. Agric. Food Chem. 2016 64 151 160 10.1021/acs.jafc.5b04861 26646558 393. Yoon S.Y. Hong G.H. Kwon H.S. Park S. Park S.Y. Shin B. Kim T.B. Moon H.B. Cho Y.S. S-adenosylmethionine reduces airway inflammation and fibrosis in a murine model of chronic severe asthma via suppression of oxidative stress Exp. Mol. Med. 2016 48 e236 10.1038/emm.2016.35 27256110 394. Tlili M. Rouatbi S. Sriha B. Ben Rhouma K. Sakly M. Vaudry D. Wurtz O. Tebourbi O. Pituitary Adenylate Cyclase-Activating Polypeptide Reverses Ammonium Metavanadate-Induced Airway Hyperresponsiveness in Rats Oxid. Med. Cell. Longev. 2015 2015 787561 10.1155/2015/787561 26199679 395. Gong J.H. Shin D. Han S.Y. Park S.H. Kang M.K. Kim J.L. Kang Y.H. Blockade of airway inflammation by kaempferol via disturbing Tyk-STAT signaling in airway epithelial cells and in asthmatic mice Evid. Based Complement. Altern. Med. 2013 2013 250725 10.1155/2013/250725 396. Liu H. Xue J.X. Li X. Ao R. Lu Y. Quercetin liposomes protect against radiation-induced pulmonary injury in a murine model Oncol. Lett. 2013 6 453 459 10.3892/ol.2013.1365 24137346 397. Huang R. Zhong T. Wu H. Quercetin protects against lipopolysaccharide-induced acute lung injury in rats through suppression of inflammation and oxidative stress Arch. Med. Sci. 2015 11 427 432 10.5114/aoms.2015.50975 25995762 398. Yasui M. Matsushima M. Omura A. Mori K. Ogasawara N. Kodera Y. Shiga M. Ito K. Kojima S. Kawabe T. The Suppressive Effect of Quercetin on Toll-Like Receptor 7-Mediated Activation in Alveolar Macrophages Pharmacology 2015 96 201 209 10.1159/000438993 26329008 399. Zhang M. Lin J.M. Li X.S. Li J. Quercetin ameliorates LPS-induced inflammation in human peripheral blood mononuclear cells by inhibition of the TLR2-NF-κB pathway Genet. Mol. Res. 2016 15 15028297 10.4238/gmr.15028297 400. Takeda K. Miyahara N. Matsubara S. Taube C. Kitamura K. Hirano A. Tanimoto M. Gelfand E.W. Immunomodulatory effects of ambroxol on airway hyperresponsiveness and inflammation Immune Netw. 2016 16 165 175 10.4110/in.2016.16.3.165 27340385 401. Raju K.R.S. Kumar M.N.S. Gupta S. Naga S.T. Shankar J.K. Murthy V. Madhunapanthula S.R.V. Mulukutla S. Ambhore N.S. Tummala S. 5-Aminosalicylic Acid attenuates allergen-induced airway inflammation and oxidative stress in asthma Pulm. Pharmacol. Ther. 2014 29 209 216 10.1016/j.pupt.2014.07.007 25101553 402. Nader M.A. Inhibition of airway inflammation and remodeling by sitagliptin in murine chronic asthma Int. Immunopharmacol. 2015 29 761 769 10.1016/j.intimp.2015.08.043 26362207 403. Abdel-Fattah M.M. Messiha B.A.S. Salama A.A.A. Assessment of the Mechanistic Role of Cinnarizine in Modulating Experimentally-Induced Bronchial Asthma in Rats Pharmacology 2015 96 167 174 10.1159/000438705 26304475 404. Pavord I.D. Chanez P. Criner G.J. Kerstjens H.A.M. Korn S. Lugogo N. Martinot J.B. Sagara H. Albers F.C. Bradford E.S. Mepolizumab for eosinophilic chronic obstructive pulmonary disease N. Engl. J. Med. 2017 377 1613 1629 10.1056/NEJMoa1708208 28893134 405. Fernandez Romero G.A. Beros J. Criner G. Mepolizumab for the prevention of chronic obstructive pulmonary disease exacerbations Expert Rev. Respir. Med. 2019 13 125 132 10.1080/17476348.2019.1561287 30570418 406. Criner G.J. Celli B.R. Brightling C.E. Agusti A. Papi A. Singh D. Sin D.D. Vogelmeier C.F. Sciurba F.C. Bafadhel M. Benralizumab for the prevention of COPD exacerbations N. Engl. J. Med. 2019 381 1023 1034 10.1056/NEJMoa1905248 31112385 407. Brightling C.E. Bleecker E.R. Panettieri R.A. Bafadhel M. She D. Ward C.K. Xu X. Birrell C. van der Merwe R. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: A randomised, double-blind, placebo-controlled, phase 2a study Lancet Respir. Med. 2014 2 891 901 10.1016/S2213-2600(14)70187-0 25208464 408. NCT02138916 Benralizumab Efficacy in Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) With Exacerbation History—Full Text View—ClinicalTrials.gov 2019 Available online: https://clinicaltrials.gov/show/NCT02138916 (accessed on 2 May 2020) 409. Barnes P.J. New anti-inflammatory targets for chronic obstructive pulmonary disease Nat. Rev. Drug Discov. 2013 12 543 559 10.1038/nrd4025 23977698 410. Global Initiative for Chronic Obstructive Lung Disease: Pocket Guide To COPD Diagnosis, Management, and Prevention, A Guide for Health Care Professionals 2017 Report Available online: https://goldcopd.org/wp-content/uploads/2016/12/wms-GOLD-2017-Pocket-Guide.pdf (accessed on 25 September 2020) 411. Yang I.A. Clarke M.S. Sim E.H. Fong K.M. Inhaled corticosteroids for stable chronic obstructive pulmonary disease Cochrane Database Syst. Rev. 2012 2012 CD002991 10.1002/14651858.CD002991.pub3 412. Nannini L.J. Poole P. Milan S.J. Holmes R. Normansell R. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease Cochrane Database Syst. Rev. 2013 2017 CD003794 10.1002/14651858.CD003794.pub4 413. Calzetta L. Di Marco F. Blasi F. Cazzola M. Centanni S. Micheletto C. Rossi A. Rogliani P. Impact of ICS/LABA and LABA/LAMA FDCs on functional and clinical outcomes in COPD: A network meta-analysis Pulm. Pharmacol. Ther. 2019 59 101855 10.1016/j.pupt.2019.101855 31639476 414. Barnes P.J. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease J. Allergy Clin. Immunol. 2013 131 636 645 10.1016/j.jaci.2012.12.1564 23360759 415. Rennard S.I. Dale D.C. Donohue J.F. Kanniess F. Magnussen H. Sutherland E.R. Watz H. Lu S. Stryszak P. Rosenberg E. CXCR2 antagonist MK-7123 a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease Am. J. Respir. Crit. Care Med. 2015 191 1001 1011 10.1164/rccm.201405-0992OC 25695403 416. Barreiro E. Wang X. Tang J. COPD: Preclinical models and emerging therapeutic targets Expert Opin. Ther. Targets 2019 23 829 838 10.1080/14728222.2019.1667976 31512957 417. Paul T. Salazar-Degracia A. Peinado V.I. Tura-Ceide O. Blanco I. Barreiro E. Barberà J.A. Soluble guanylate cyclase stimulation reduces oxidative stress in experimental Chronic Obstructive Pulmonary Disease PLoS ONE 2018 13 e0190628 10.1371/journal.pone.0190628 29304131 418. Barreiro E. Puig-Vilanova E. Marin-Corral J. Chacón-Cabrera A. Salazar-Degracia A. Mateu X. Puente-Maestu L. García-Arumí E. Andreu A.L. Molina L. Therapeutic Approaches in Mitochondrial Dysfunction, Proteolysis, and Structural Alterations of Diaphragm and Gastrocnemius in Rats With Chronic Heart Failure J. Cell. Physiol. 2016 231 1495 1513 10.1002/jcp.25241 26530247 419. Brasier A.R. Therapeutic targets for inflammation-mediated airway remodeling in chronic lung disease Expert Rev. Respir. Med. 2018 12 931 939 10.1080/17476348.2018.1526677 30241450 420. Liu Z. Tian B. Chen H. Wang P. Brasier A.R. Zhou J. Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation Eur. J. Med. Chem. 2018 151 450 461 10.1016/j.ejmech.2018.04.006 29649741 421. Liu Z. Wang P. Chen H. Wold E.A. Tian B. Brasier A.R. Zhou J. Drug Discovery Targeting Bromodomain-Containing Protein 4 J. Med. Chem. 2017 60 4533 4558 10.1021/acs.jmedchem.6b01761 28195723 422. Broekman W. Khedoe P.P.S.J. Schepers K. Roelofs H. Stolk J. Hiemstra P.S. Mesenchymal stromal cells: A novel therapy for the treatment of chronic obstructive pulmonary disease? Thorax 2018 73 565 574 10.1136/thoraxjnl-2017-210672 29653970 423. Raghu G. Pharmacotherapy for idiopathic pulmonary fibrosis: Current landscape and future potential Eur. Respir. Rev. 2017 26 170071 10.1183/16000617.0071-2017 28954769 424. Margaritopoulos G.A. Trachalaki A. Wells A.U. Vasarmidi E. Bibaki E. Papastratigakis G. Detorakis S. Tzanakis N. Antoniou K.M. Pirfenidone improves survival in IPF: Results from a real-life study BMC Pulm. Med. 2018 18 177 10.1186/s12890-018-0736-z 30470213 425. Somogyi V. Chaudhuri N. Torrisi S.E. Kahn N. Müller V. Kreuter M. The therapy of idiopathic pulmonary fibrosis: What is next? Eur. Respir. Rev. 2019 28 190021 10.1183/16000617.0021-2019 31484664 426. Lederer D.J. Martinez F.J. Idiopathic Pulmonary Fibrosis N. Engl. J. Med. 2018 378 1811 1823 10.1056/NEJMra1705751 29742380 427. Murray L.A. Rosada R. Moreira A.P. Joshi A. Kramer M.S. Hesson D.P. Argentieri R.L. Mathai S. Gulati M. Herzog E.L. Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages PLoS ONE 2010 5 e9683 10.1371/journal.pone.0009683 20300636 428. Santhiago M.R. Singh V. Barbosa F.L. Agrawal V. Wilson S.E. Monocyte development inhibitor PRM-151 decreases corneal myofibroblast generation in rabbits Exp. Eye Res. 2011 93 786 789 10.1016/j.exer.2011.08.015 21933674 429. Van Den Blink B. Dillingh M.R. Ginns L.C. Morrison L.D. Moerland M. Wijsenbeek M. Trehu E.G. Bartholmai B.J. Burggraaf J. Recombinant human pentraxin-2 therapy in patients with idiopathic pulmonary fibrosis: Safety, pharmacokinetics and exploratory efficacy Eur. Respir. J. 2016 47 889 897 10.1183/13993003.00850-2015 26869678 430. Raghu G. Van Den Blink B. Hamblin M.J. Whitney Brown A. Golden J.A. Ho L.A. Wijsenbeek M.S. Vasakova M. Pesci A. Antin-Ozerkis D.E. Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis a randomized clinical trial JAMA J. Am. Med. Assoc. 2018 319 2299 2307 10.1001/jama.2018.6129 29800034 431. Raghu G. van den Blink B. Hamblin M.J. Brown A.W. Golden J.A. Ho L.A. Wijsenbeek M.S. Vasakova M. Pesci A. Antin-Ozerkis D.E. Long-term treatment with recombinant human pentraxin 2 protein in patients with idiopathic pulmonary fibrosis: An open-label extension study Lancet Respir. Med. 2019 7 657 664 10.1016/S2213-2600(19)30172-9 31122893 432. NCT01890265 Evaluate the Safety and Efficacy of FG-3019 (Pamrevlumab) in Participants With Idiopathic Pulmonary Fibrosis (IPF)—Full Text View—ClinicalTrials.gov 2020 Available online: https://clinicaltrials.gov/show/NCT01890265 (accessed on 20 September 2020) 433. Gorina E. Richeldi L. Raghu G. Fernandez Perez E. Costabel U. Albera C. Lederer D. Flaherty K. Ettinger N. Bercz P. PRAISE, a randomized, placebo-controlled, double-blind Phase 2 clinical trial of pamrevlumab (FG-3019) in IPF patients Eur. Respir. J. 2017 50 OA3400 434. Gagnon L. Leduc M. Thibodeau J.F. Zhang M.Z. Grouix B. Sarra-Bournet F. Gagnon W. Hince K. Tremblay M. Geerts L. A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84 Am. J. Pathol. 2018 188 1132 1148 10.1016/j.ajpath.2018.01.009 29454750 435. Khalil N. Manganas H. Ryerson C.J. Shapera S. Cantin A.M. Hernandez P. Turcotte E.E. Parker J.M. Moran J.E. Albert G.R. Phase 2 clinical trial of PBI-4050 in patients with idiopathic pulmonary fibrosis Eur. Respir. J. 2019 53 1800663 10.1183/13993003.00663-2018 30578394 436. NCT02738801 Study to Assess Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of GLPG1690 2017 Available online: https://clinicaltrials.gov/show/NCT02738801 (accessed on 20 September 2020) 437. Maher T.M. van der Aar E.M. Van de Steen O. Allamassey L. Desrivot J. Dupont S. Fagard L. Ford P. Fieuw A. Wuyts W. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): A phase 2a randomised placebo-controlled trial Lancet Respir. Med. 2018 6 627 635 10.1016/S2213-2600(18)30181-4 29792287 438. Maher T.M. Kreuter M. Lederer D.J. Brown K.K. Wuyts W. Verbruggen N. Stutvoet S. Fieuw A. Ford P. Abi-Saab W. Rationale, design and objectives of two phase III, randomised, placebo-controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2) BMJ Open Respir. Res. 2019 6 e000422 10.1136/bmjresp-2019-000422 439. Peters-Golden M. Henderson W.R. University of Michigan Health Sys-tem, 6301 MSRB III, 1150 W. Medical Cen-ter Dr N. Engl. J. Med. 2007 357 1841 1854 10.1056/NEJMra071371 17978293 440. Izumo T. Kondo M. Nagai A. Effects of a leukotriene B4 receptor antagonist on bleomycin-induced pulmonary fibrosis Eur. Respir. J. 2009 34 1444 1451 10.1183/09031936.00143708 19460787 441. NCT02503657 Safety and Tolerability Study in Subjects With Idiopathic Pulmonary Fibrosis (IPF)—Full Text View—ClinicalTrials.gov 2020 Available online: https://clinicaltrials.gov/show/NCT02503657 (accessed on 20 September 2020) 442. NCT02688647 A Study to Evaluate the Safety, Tolerability, and Activity of KD025 in Subjects With Idiopathic Pulmonary Fibrosis 2019 Available online: https://clinicaltrials.gov/show/NCT02688647 (accessed on 20 September 2020) 443. Zanin-Zhorov A. Weiss J.M. Nyuydzefe M.S. Chen W. Scher J.U. Mo R. Depoil D. Rao N. Liu B. Wei J. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism Proc. Natl. Acad. Sci. USA 2014 111 16814 16819 10.1073/pnas.1414189111 25385601 444. NCT03142191 A Study to Evaluate the Efficacy and Safety of CC-90001 in Subjects With Idiopathic Pulmonary Fibrosis—Full Text View—ClinicalTrials.gov 2020 Available online: https://clinicaltrials.gov/show/NCT03142191 (accessed on 20 September 2020) 445. van der Velden J.L.J. Ye Y. Nolin J.D. Hoffman S.M. Chapman D.G. Lahue K.G. Abdalla S. Chen P. Liu Y. Bennett B. JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers Clin. Transl. Med. 2016 5 36 10.1186/s40169-016-0117-2 27590145 446. Horan G.S. Wood S. Ona V. Dan J.L. Lukashev M.E. Weinreb P.H. Simon K.J. Hahm K. Allaire N.E. Rinaldi N.J. Partial inhibition of integrin αvβ6 prevents pulmonary fibrosis without exacerbating inflammation Am. J. Respir. Crit. Care Med. 2008 177 56 65 10.1164/rccm.200706-805OC 17916809 447. NCT01371305 STX-100 in Patients With Idiopathic Pulmonary Fibrosis (IPF)—Full Text View—ClinicalTrials.gov 2020 Available online: https://clinicaltrials.gov/show/NCT01371305 (accessed on 20 September 2020) 448. Zhang X.L. Xing R.G. Chen L. Liu C.R. Miao Z.G. PI3K/Akt signaling is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis via regulation of epithelial-mesenchymal transition Mol. Med. Rep. 2016 14 5699 5706 10.3892/mmr.2016.5960 27878273 449. NCT01725139 A Proof of Mechanism Study With GSK2126458 in Patients With Idiopathic Pulmonary Fibrosis (IPF)—Full Text View—ClinicalTrials.gov 2019 Available online: https://clinicaltrials.gov/show/NCT01725139 (accessed on 20 September 2020) 450. Mercer P.F. Woodcock H.V. Eley J.D. Platé M. Sulikowski M.G. Durrenberger P.F. Franklin L. Nanthakumar C.B. Man Y. Genovese F. Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF Thorax 2016 71 701 711 10.1136/thoraxjnl-2015-207429 27103349 451. Lukey P.T. Harrison S.A. Yang S. Man Y. Holman B.F. Rashidnasab A. Azzopardi G. Grayer M. Simpson J.K. Bareille P. A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis Eur. Respir. J. 2019 53 1801992 10.1183/13993003.01992-2018 30765508 452. NCT01462006 Double-blind Placebo-controlled Pilot Study of Sirolimus in Idiopathic Pulmonary Fibrosis (IPF) 2018 Available online: https://clinicaltrials.gov/show/NCT01462006 (accessed on 20 September 2020) 453. NCT01969409 Autoantibody Reduction Therapy in Patients With Idiopathic Pulmonary Fibrosis 2020 Available online: https://clinicaltrials.gov/show/NCT01969409 (accessed on 20 September 2020) 454. NCT01266317 Combined PEX, Rituximab and Steroids in Acute Idiopathic Pulmonary Fibrosis Exacerbations—Full Text View—ClinicalTrials.gov 2018 Available online: https://clinicaltrials.gov/show/NCT01266317 (accessed on 20 September 2020) 455. Donahoe M. Valentine V.G. Chien N. Gibson K.F. Raval J.S. Saul M. Xue J. Zhang Y. Duncan S.R. Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis PLoS ONE 2015 10 e0127771 26083430 456. NCT01777737 Study to Test the Validity of the Treatment of Idiopathic Pulmonary Fibrosis With Cotrimoxazole 2017 Available online: https://clinicaltrials.gov/show/nct01777737 (accessed on 20 September 2020) 457. NCT01872689 A Study of Lebrikizumab in Patients With Idiopathic Pulmonary Fibrosis—Full Text View—ClinicalTrials.gov 2018 5 7 Available online: https://clinicaltrials.gov/show/NCT01872689 (accessed on 20 September 2020) 458. NCT01629667 A Phase 2, Randomized Dose-ranging Study to Evaluate the Efficacy of Tralokinumab in Adults With Idiopathic Pulmonary Fibrosis—Full Text View—ClinicalTrials.gov 2017 Available online: https://clinicaltrials.gov/show/NCT01629667 (accessed on 20 September 2020) 459. NCT02173145 Azithromycin in Idiopathic Pulmonary Fibrosis—Full Text View—ClinicalTrials.gov 2019 Available online: https://clinicaltrials.gov/show/NCT02173145 (accessed on 20 September 2020) 460. Cazzola M. Matera M.G. Rogliani P. Calzetta L. Senolytic drugs in respiratory medicine: Is it an appropriate therapeutic approach? Expert Opin. Investig. Drugs 2018 27 573 581 10.1080/13543784.2018.1492548 461. Malayeri A.R. Hemmati A.A. Arzi A. Rezaie A. Ghafurian-Boroojerdnia M. Khalili H.R. A comparison of the effects of quercetin hydrate with those of vitamin E on the levels of IL-13, PDGF, TNF-α, and INF- γ in bleomycin-induced pulmonary fibrosis in rats Jundishapur J. Nat. Pharm. Prod. 2016 11 10.17795/jjnpp-27705 462. Schafer M.J. White T.A. Iijima K. Haak A.J. Ligresti G. Atkinson E.J. Oberg A.L. Birch J. Salmonowicz H. Zhu Y. Cellular senescence mediates fibrotic pulmonary disease Nat. Commun. 2017 8 14532 10.1038/ncomms14532 28230051 463. Lehmann M. Korfei M. Mutze K. Klee S. Skronska-Wasek W. Alsafadi H.N. Ota C. Costa R. Schiller H.B. Lindner M. Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo Eur. Respir. J. 2017 50 1602367 10.1183/13993003.02367-2016 28775044 464. Barkauskas C.E. Cronce M.J. Rackley C.R. Bowie E.J. Keene D.R. Stripp B.R. Randell S.H. Noble P.W. Hogan B.L.M. Type 2 alveolar cells are stem cells in adult lung J. Clin. Investig. 2013 123 3025 3036 10.1172/JCI68782 23921127 465. Sisson T.H. Mendez M. Choi K. Subbotina N. Courey A. Cunningham A. Dave A. Engelhardt J.F. Liu X. White E.S. Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis Am. J. Respir. Crit. Care Med. 2010 181 254 263 10.1164/rccm.200810-1615OC 19850947 466. Martyanov V. Kim G.H.J. Hayes W. Du S. Ganguly B.J. Sy O. Lee S.K. Bogatkevich G.S. Schieven G.L. Schiopu E. Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease PLoS ONE 2017 12 e0187580 10.1371/journal.pone.0187580 29121645 467. Guignabert C. Phan C. Seferian A. Huertas A. Tu L. Thuillet R. Sattler C. Le Hiress M. Tamura Y. Jutant E.M. Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension J. Clin. Investig. 2016 126 3207 3218 10.1172/JCI86249 27482885 468. Mailleux A.A. Crestani B. Licence to kill senescent cells in idiopathic pulmonary fibrosis? Eur. Respir. J. 2017 50 1701360 10.1183/13993003.01360-2017 28775054 469. Banerjee E.R. Kar S. Konsam S. Hore G. Mitra S. Biswas S. Sinha A. Jana N.R. Therapeutic use of fisetin, curcumin, and mesoporous carbon nanoparticle loaded fisetin in bleomycin-induced idiopathic pulmonary fibrosis Biomed. Res. Ther. 2015 2 250 262 10.7603/s40730-015-0010-4 470. Pan J. Li D. Xu Y. Zhang J. Wang Y. Chen M. Lin S. Huang L. Chung E.J. Citrin D.E. Inhibition of Bcl-2/xl With ABT-263 Selectively Kills Senescent Type II Pneumocytes and Reverses Persistent Pulmonary Fibrosis Induced by Ionizing Radiation in Mice Int. J. Radiat. Oncol. Biol. Phys. 2017 99 353 361 10.1016/j.ijrobp.2017.02.216 28479002 471. Justice J.N. Nambiar A.M. Tchkonia T. LeBrasseur N.K. Pascual R. Hashmi S.K. Prata L. Masternak M.M. Kritchevsky S.B. Musi N. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study EBioMedicine 2019 40 554 563 10.1016/j.ebiom.2018.12.052 30616998 472. Habib A.R.R. Kajbafzadeh M. Desai S. Yang C.L. Skolnik K. Quon B.S. A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis Sci. Rep. 2019 9 7234 10.1038/s41598-019-43652-2 31076617 473. Clancy J.P. Cotton C.U. Donaldson S.H. Solomon G.M. VanDevanter D.R. Boyle M.P. Gentzsch M. Nick J.A. Illek B. Wallenburg J.C. CFTR modulator theratyping: Current status, gaps and future directions J. Cyst. Fibros. 2019 18 22 34 10.1016/j.jcf.2018.05.004 29934203 474. Lopes-Pacheco M. CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine Front. Pharmacol. 2020 10 1662 10.3389/fphar.2019.01662 32153386 475. Lopes-Pacheco M. CFTR modulators: Shedding light on precision medicine for cystic fibrosis Front. Pharmacol. 2016 7 275 10.3389/fphar.2016.00275 27656143 476. Li H. Pesce E. Sheppard D.N. Singh A.K. Pedemonte N. Therapeutic approaches to CFTR dysfunction: From discovery to drug development J. Cyst. Fibros. 2018 17 S14 S21 10.1016/j.jcf.2017.08.013 28916430 477. Van Goor F. Hadida S. Grootenhuis P.D.J. Burton B. Stack J.H. Straley K.S. Decker C.J. Miller M. McCartney J. Olson E.R. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809 Proc. Natl. Acad. Sci. USA 2011 108 18843 18848 10.1073/pnas.1105787108 21976485 478. Ratjen F. Hug C. Marigowda G. Tian S. Huang X. Stanojevic S. Milla C.E. Robinson P.D. Waltz D. Davies J.C. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: A randomised, placebo-controlled phase 3 trial Lancet Respir. Med. 2017 5 557 567 10.1016/S2213-2600(17)30215-1 28606620 479. Konstan M.W. McKone E.F. Moss R.B. Marigowda G. Tian S. Waltz D. Huang X. Lubarsky B. Rubin J. Millar S.J. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): A phase 3, extension study Lancet Respir. Med. 2017 5 107 118 10.1016/S2213-2600(16)30427-1 28011037 480. Wainwright C.E. Elborn J.S. Ramsey B.W. Marigowda G. Huang X. Cipolli M. Colombo C. Davies J.C. De Boeck K. Flume P.A. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del CFTR N. Engl. J. Med. 2015 373 220 231 10.1056/NEJMoa1409547 25981758 481. McElvaney O.J. Gunaratnam C. McElvaney O.F. Bagwe I. Reeves E.P. McElvaney N.G. Emerging pharmacotherapies in cystic fibrosis Expert Rev. Respir. Med. 2018 12 843 855 10.1080/17476348.2018.1512409 30129380 482. Pedemonte N. Lukacs G.L. Du K. Caci E. Zegarra-Moran O. Galietta L.J.V. Verkman A.S. Small-molecule correctors of defective ΔF508-CFTR cellular processing identified by high-throughput screening J. Clin. Investig. 2005 115 2564 2571 10.1172/JCI24898 16127463 483. Phuan P.W. Veit G. Tan J.A. Finkbeiner W.E. Lukacs G.L. Verkman A.S. Potentiators of defective DF508-CFTR gating that do not interfere with corrector action Mol. Pharmacol. 2015 88 791 799 10.1124/mol.115.099689 26245207 484. Liang F. Shang H. Jordan N.J. Wong E. Mercadante D. Saltz J. Mahiou J. Bihler H.J. Mense M. High-Throughput Screening for Readthrough Modulators of CFTR PTC Mutations SLAS Technol. 2017 22 315 324 10.1177/2472630317692561 28376702 485. Giuliano K.A. Wachi S. Drew L. Dukovski D. Green O. Bastos C. Cullen M.D. Hauck S. Tait B.D. Munoz B. Use of a High-Throughput Phenotypic Screening Strategy to Identify Amplifiers, a Novel Pharmacological Class of Small Molecules That Exhibit Functional Synergy with Potentiators and Correctors SLAS Discov. 2018 23 111 121 10.1177/2472555217729790 28898585 486. Van Der Plas S.E. Kelgtermans H. De Munck T. Martina S.L.X. Dropsit S. Quinton E. De Blieck A. Joannesse C. Tomaskovic L. Jans M. Discovery of N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-lH-pyrazole-5-carboxamide (GLPG1837), a Novel Potentiator Which Can Open Class III Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels to a High J. Med. Chem. 2018 61 1425 1435 10.1021/acs.jmedchem.7b01288 29148763 487. Veit G. Xu H. Dreano E. Avramescu R.G. Bagdany M. Beitel L.K. Roldan A. Hancock M.A. Lay C. Li W. Structure-guided combination therapy to potently improve the function of mutant CFTRs Nat. Med. 2018 24 1732 1742 10.1038/s41591-018-0200-x 30297908 488. Wang X. Liu B. Searle X. Yeung C. Bogdan A. Greszler S. Singh A. Fan Y. Swensen A.M. Vortherms T. Discovery of 4-[(2R,4R)-4-({[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic Acid (ABBV/GLPG-2222), a Potent Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Corrector for J. Med. Chem. 2018 61 1436 1449 10.1021/acs.jmedchem.7b01339 29251932 489. Berg A. Hallowell S. Tibbetts M. Beasley C. Brown-Phillips T. Healy A. Pustilnik L. Doyonnas R. Pregel M. High-Throughput Surface Liquid Absorption and Secretion Assays to Identify F508del CFTR Correctors Using Patient Primary Airway Epithelial Cultures SLAS Discov. 2019 24 724 737 10.1177/2472555219849375 31107611 490. De Wilde G. Gees M. Musch S. Verdonck K. Jans M. Wesse A.S. Singh A.K. Hwang T.C. Christophe T. Pizzonero M. Identification of GLPG/ABBV-2737, a novel class of corrector, which exerts functional synergy with other CFTR modulators Front. Pharmacol. 2019 10 514 10.3389/fphar.2019.00514 31143125 491. Merkert S. Schubert M. Olmer R. Engels L. Radetzki S. Veltman M. Scholte B.J. Zöllner J. Pedemonte N. Galietta L.J.V. High-Throughput Screening for Modulators of CFTR Activity Based on Genetically Engineered Cystic Fibrosis Disease-Specific iPSCs Stem Cell Rep. 2019 12 1389 1403 10.1016/j.stemcr.2019.04.014 492. Rafeeq M.M. Murad H.A.S. Cystic fibrosis: Current therapeutic targets and future approaches J. Transl. Med. 2017 15 84 10.1186/s12967-017-1193-9 28449677 493. Cheng K. Ashby D. Smyth R.L. Oral steroids for long-term use in cystic fibrosis Cochrane Database Syst. Rev. 2015 2015 CD000407 10.1002/14651858.CD000407.pub4 494. Balfour-Lynn I.M. Welch K. Smith S. Inhaled corticosteroids for cystic fibrosis Cochrane Database Syst. Rev. 2019 2019 CD001915 10.1002/14651858.CD001915.pub6 31271656 495. Ross K.R. Chmiel J.F. Konstan M.W. The role of inhaled corticosteroids in the management of cystic fibrosis Pediatr. Drugs 2009 11 101 113 10.2165/00148581-200911020-00002 19301932 496. Lands L.C. Stanojevic S. Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis Cochrane Database Syst. Rev. 2019 2019 CD001505 10.1002/14651858.CD001505.pub5 31499593 497. Konstan M.W. VanDevanter D.R. Sawicki G.S. Pasta D.J. Foreman A.J. Neiman E.A. Morgan W.J. Association of high-dose ibuprofen use, lung function decline, and long-term survival in children with cystic fibrosis Ann. Am. Thorac. Soc. 2018 15 485 493 10.1513/AnnalsATS.201706-486OC 29313709 498. Konstan M.W. Döring G. Heltshe S.L. Lands L.C. Hilliard K.A. Koker P. Bhattacharya S. Staab A. Hamilton A. A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis J. Cyst. Fibros. 2014 13 148 155 10.1016/j.jcf.2013.12.009 24440167 499. Elborn J.S. Bhatt L. Grosswald R. Ahuja S. Springman E.B. Phase I Studies of Acebilustat: Pharmacokinetics, Pharmacodynamics, Food Effect, and CYP3A Induction Clin. Transl. Sci. 2017 10 20 27 10.1111/cts.12426 27792868 500. Elborn J.S. Ahuja S. Springman E. Mershon J. Grosswald R. Rowe S.M. EMPIRE-CF: A phase II randomized placebo-controlled trial of once-daily, oral acebilustat in adult patients with cystic fibrosis—Study design and patient demographics Contemp. Clin. Trials 2018 72 86 94 10.1016/j.cct.2018.07.014 30056216 501. NCT02759562 Effect of Andecaliximab on FEV1 in Adults With Cystic Fibrosis—Full Text View—ClinicalTrials.gov 2018 Available online: https://clinicaltrials.gov/show/NCT02759562 (accessed on 3 May 2020) 502. NCT03748199 Clinical Study to Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of POL6014 in Patients with CF—Full Text View—ClinicalTrials.gov 2018 Available online: https://clinicaltrials.gov/show/NCT03748199 (accessed on 3 May 2020) 503. McElvaney N.G. Alpha-1 antitrypsin therapy in cystic fibrosis and the lung disease associated with alpha-1 antitrypsin deficiency Ann. Am. Thorac. Soc. 2016 13 S191 S196 27115956 504. Elborn J.S. Perrett J. Forsman-Semb K. Marks-Konczalik J. Gunawardena K. Entwistle N. Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis Eur. Respir. J. 2012 40 969 976 10.1183/09031936.00194611 22267768 505. Motwani M. Bennett F. Tepper M. White B. Norris P. MacAllister R. Serhan C. Gilroy D. Anabasum (JBT-101) enhances resolution of inflammation in humans Arthritis Rheumatol. 2017 69 Suppl. 10 Available online: https://acrabstracts.org/abstract/anabasum-jbt-101-enhances-resolution-of-inflammation-in-humans/ (accessed on 7 December 2020) 506. NCT02465450 Safety, Tolerability, Pharmacokinetics, and Efficacy of JBT-101 (Lenabasum) in Cystic Fibrosis—Full Text View—ClinicalTrials.gov Available online: https://clinicaltrials.gov/ct2/show/NCT02465450 (accessed on 20 September 2020) 507. Burstein S.H. Ajulemic acid: Potential treatment for chronic inflammation Pharmacol. Res. Perspect. 2018 6 e00394 10.1002/prp2.394 29638269 508. Pertwee R.G. Endocannabinoids and their pharmacological actions Handbook of Experimental Pharmacology Springer New York, NY, USA 2015 Volume 231 1 37 509. Gkoumassi E. Dekkers B.G.J. Dröge M.J. Elzinga C.R.S. Schmidt M. Meurs H. Zaagsma J. Nelemans S.A. Virodhamine and CP55,940 modulate cAMP production and IL-8 release in human bronchial epithelial cells Br. J. Pharmacol. 2007 151 1041 1048 10.1038/sj.bjp.0707320 17558435 510. McElvaney N.G. Hubbard R.C. Birrer P. Crystal R.G. Chernick M.S. Frank M.M. Caplan D.B. Aerosol α1 -antitrypsin treatment for cystic fibrosis Lancet 1991 337 392 394 10.1016/0140-6736(91)91167-S 1671425 511. Griese M. Latzin P. Kappler M. Weckerle K. Heinzimaier T. Bernhardt T. Hartl D. α1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients Eur. Respir. J. 2007 29 240 250 10.1183/09031936.00047306 17050563 512. Grimbert D. Vecellio L. Delépine P. Attucci S. Boissinot E. Poncin A. Gauthier F. Valat C. Saudubray F. Antonioz P. Characteristics of EPI-hNE4 aerosol: A new elastase inhibitor for treatment of cystic fibrosis J. Aerosol Med. Depos. Clear. Eff. Lung 2003 16 121 129 10.1089/089426803321919889 513. Williams B. Robinette M. Slovis B. Deretci V. Perkett E. Hydroxychloroquine—Pilot study of anti-inflammatory effects in cystic fibrosis Pediatr. Pulmonol. 2008 43 314 514. Moss R.B. Mistry S.J. Konstan M.W. Pilewski J.M. Kerem E. Tal-Singer R. Lazaar A.L. Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis J. Cyst. Fibros. 2013 12 241 248 10.1016/j.jcf.2012.08.016 22995323 515. Ballmann M. Junge S. von der Hardt H. Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis Respir. Med. 2003 97 498 500 10.1053/rmed.2002.1471 12735666 516. McElvaney O.J. McElvaney N.G. Targeting IL-8 in cystic fibrosis: Enough but not too much Am. J. Respir. Cell Mol. Biol. 2018 59 401 402 10.1165/rcmb.2018-0145ED 29723035 517. McElvaney O.J. O’Reilly N. White M. Lacey N. Pohl K. Gerlza T. Bergin D.A. Kerr H. McCarthy C. O’Brien M.E. The effect of the decoy molecule PA401 on CXCL8 levels in bronchoalveolar lavage fluid of patients with cystic fibrosis Mol. Immunol. 2015 63 550 558 10.1016/j.molimm.2014.10.013 25453468 518. Karp C.L. Flick L.M. Park K.W. Softic S. Greer T.M. Keledjian R. Yang R. Uddin J. Guggino W.B. Atabani S.F. Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway Nat. Immunol. 2004 5 388 392 10.1038/ni1056 15034576 519. József L. Zouki C. Petasis N.A. Serhan C.N. Filep J.G. Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit peroxynitrite formation, NF-κB and AP-1 activation, and IL-8 gene expression in human leukocytes Proc. Natl. Acad. Sci. USA 2002 99 13266 13271 10.1073/pnas.202296999 12235371 520. Nagaoka I. Tamura H. Hirata M. An Antimicrobial Cathelicidin Peptide, Human CAP18/LL-37, Suppresses Neutrophil Apoptosis via the Activation of Formyl-Peptide Receptor-Like 1 and P2X 7 J. Immunol. 2006 176 3044 3052 10.4049/jimmunol.176.5.3044 16493063 521. Herrera B.S. Hasturk H. Kantarci A. Freire M.O. Nguyen O. Kansal S. van Dyke T.E. Impact of resolvin E1 on murine neutrophil phagocytosis in type 2 diabetes Infect. Immun. 2015 83 792 801 10.1128/IAI.02444-14 25486994 522. Freire M.O. Dalli J. Serhan C.N. Van Dyke T.E. Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes J. Immunol. 2017 198 718 728 10.4049/jimmunol.1601543 27994073 523. Kurihara T. Jones C.N. Yu Y.M. Fischman A.J. Watada S. Tompkins R.G. Fagan S.P. Irimia D. Resolvin D2 restores neutrophil directionality and improves survival after burns FASEB J. 2013 27 2270 2281 10.1096/fj.12-219519 23430978 524. Schwab J.M. Chiang N. Arita M. Serhan C.N. Resolvin E1 and protectin D1 activate inflammation-resolution programmes Nature 2007 447 869 874 10.1038/nature05877 17568749 525. Hsiao H.-M. Thatcher T.H. Levy E.P. Fulton R.A. Owens K.M. Phipps R.P. Sime P.J. Resolvin D1 Attenuates Polyinosinic-Polycytidylic Acid–Induced Inflammatory Signaling in Human Airway Epithelial Cells via TAK1 J. Immunol. 2014 193 4980 4987 10.4049/jimmunol.1400313 25320283 526. Ringholz F.C. Higgins G. Hatton A. Sassi A. Moukachar A. Fustero-Torre C. Hollenhorst M. Sermet-Gaudelus I. Harvey B.J. McNally P. Resolvin D1 regulates epithelial ion transport and inflammation in cystic fibrosis airways J. Cyst. Fibros. 2018 17 607 615 10.1016/j.jcf.2017.11.017 29233471 527. NCT03265288 Study of LAU-7b in the Treatment of Cystic Fibrosis in Adults—Full Text View—ClinicalTrials.gov 2020 Available online: https://clinicaltrials.gov/show/NCT03265288 (accessed on 3 May 2020) 528. Kontoghiorghes G.J. Kontoghiorghe C.N. Prospects for the introduction of targeted antioxidant drugs for the prevention and treatment of diseases related to free radical pathology Expert Opin. Investig. Drugs 2019 28 593 603 10.1080/13543784.2019.1631284 529. Cantin A.M. Low-hanging fruit and antioxidant therapy in cystic fibrosis Am. J. Respir. Crit. Care Med. 2018 198 555 557 10.1164/rccm.201805-0872ED 29847144 530. Calabrese C. Tosco A. Abete P. Carnovale V. Basile C. Magliocca A. Quattrucci S. De Sanctis S. Alatri F. Mazzarella G. Randomized, single blind, controlled trial of inhaled glutathione vs placebo in patients with cystic fibrosis J. Cyst. Fibros. 2015 14 203 210 10.1016/j.jcf.2014.09.014 25458463 531. Skov M. Pressler T. Lykkesfeldt J. Poulsen H.E. Jensen P.Ø. Johansen H.K. Qvist T. Kræmer D. Høiby N. Ciofu O. The effect of short-term, high-dose oral N-acetylcysteine treatment on oxidative stress markers in cystic fibrosis patients with chronic P. aeruginosa infection—A pilot study J. Cyst. Fibros. 2015 14 211 218 10.1016/j.jcf.2014.09.015 25458464 532. Hector A. Griese M. Hartl D. Oxidative stress in cystic fibrosis lung disease: An early event, but worth targeting? Eur. Respir. J. 2014 44 17 19 10.1183/09031936.00038114 24982050 533. Griese M. Kappler M. Eismann C. Ballmann M. Junge S. Rietschel E. Van Koningsbruggen-Rietschel S. Staab D. Rolinck-Werninghaus C. Mellies U. Inhalation treatment with glutathione in patients with cystic fibrosis: A randomized clinical trial Am. J. Respir. Crit. Care Med. 2013 188 83 89 10.1164/rccm.201303-0427OC 23631796 534. de Vries J.J.V. Chang A.B. Bonifant C.M. Shevill E. Marchant J.M. Vitamin A and beta (β)-carotene supplementation for cystic fibrosis Cochrane Database Syst. Rev. 2018 2018 CD006751 10.1002/14651858.CD006751.pub5 535. González Jiménez D. Díaz Martín J.J. Arias Llorente R.P. Bousoño García C. Oxidative Stress in Cystic Fibrosis Cystic Fibrosis in the Light of New Research IntechOpen London, UK 2015 536. Kontoghiorghe C.N. Kolnagou A. Kontoghiorghes G.J. Antioxidant targeting by deferiprone in diseases related to oxidative damage Front. Biosci. Landmark 2014 19 862 885 10.2741/4253 537. Kontoghiorghes G.J. Prospects for introducing deferiprone as potent pharmaceutical antioxidant Front. Biosci. Elit. 2009 1 161 178 538. Conrad C. Lymp J. Thompson V. Dunn C. Davies Z. Chatfield B. Nichols D. Clancy J. Vender R. Egan M.E. Long-term treatment with oral N-acetylcysteine: Affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial J. Cyst. Fibros. 2015 14 219 227 10.1016/j.jcf.2014.08.008 25228446 539. Peters S.A. Kelly F.J. Vitamin E supplementation in cystic fibrosis J. Pediatr. Gastroenterol. Nutr. 1996 22 341 345 10.1097/00005176-199605000-00001 8732895 540. Maqbool A. Stallings V.A. Update on fat-soluble vitamins in cystic fibrosis Curr. Opin. Pulm. Med. 2008 14 574 581 10.1097/MCP.0b013e3283136787 18812835 541. Galli F. Azzi A. Present trends in vitamin E research BioFactors 2010 36 33 42 10.1002/biof.75 20108329 542. Hamahata A. Enkhbaatar P. Kraft E.R. Lange M. Leonard S.W. Traber M.G. Cox R.A. Schmalstieg F.C. Hawkins H.K. Whorton E.B. γ-Tocopherol nebulization by a lipid aerosolization device improves pulmonary function in sheep with burn and smoke inhalation injury Free Radic. Biol. Med. 2008 45 425 433 10.1016/j.freeradbiomed.2008.04.037 18503777 543. Anais J.P. Razzouq N. Carvalho M. Fernandez C. Astier A. Paul M. Astier A. Fessi H. Lorino A.M. Development of α-tocopherol acetate nanoparticles: Influence of preparative processes Drug Dev. Ind. Pharm. 2009 35 216 223 10.1080/03639040802248798 19169943 544. Rust P. Eichler I. Renner S. Elmadfa I. Long-term oral β-carotene supplementation in patients with cystic fibrosis—Effects on antioxidative status and pulmonary function Ann. Nutr. Metab. 2000 44 30 37 10.1159/000012818 10838464 545. Sagel S.D. Sontag M.K. Anthony M.M. Emmett P. Papas K.A. Effect of an antioxidant-rich multivitamin supplement in cystic fibrosis J. Cyst. Fibros. 2011 10 31 36 10.1016/j.jcf.2010.09.005 20961818 546. Papas K.A. Sontag M.K. Pardee C. Sokol R.J. Sagel S.D. Accurso F.J. Wagener J.S. A pilot study on the safety and efficacy of a novel antioxidant rich formulation in patients with cystic fibrosis J. Cyst. Fibros. 2008 7 60 67 10.1016/j.jcf.2007.05.001 17569601 547. Sagel S.D. Khan U. Jain R. Graff G. Daines C.L. Dunitz J.M. Borowitz D. Orenstein D.M. Abdulhamid I. Noe J. Effects of an antioxidant-enriched multivitamin in cystic fibrosis Am. J. Respir. Crit. Care Med. 2018 198 639 647 10.1164/rccm.201801-0105OC 29688760 548. Foucaud P. Therond P. Marchand M. Brion F. Demelier J.F. Navarro J. Selenium and vitamin E in cystic fibrosis Arch. Fr. Pediatr. 1988 45 383 386 3219038 549. Tsavachidou D. McDonnell T.J. Wen S. Wang X. Vakar-Lopez F. Pisters L.L. Pettaway C.A. Wood C.G. Do K.A. Thall P.F. Selenium and vitamin E: Cell type- and intervention-specific tissue effects in prostate cancer J. Natl. Cancer Inst. 2009 101 306 320 10.1093/jnci/djn512 19244175 550. Winklhofer-Roob B.M. Ellemunter H. Frühwirth M. Schlegel-Haueter S.E. Khoschsorur G. Van’t Hof M.A. Shmerling D.H. Plasma vitamin C concentrations in patients with cystic fibrosis: Evidence of associations with lung inflammation Am. J. Clin. Nutr. 1997 65 1858 1866 10.1093/ajcn/65.6.1858 9174484 551. Van Biervliet S. Vande Velde S. Van Biervliet J.P. Robberecht E. The effect of zinc supplements in cystic fibrosis patients Ann. Nutr. Metab. 2008 52 152 156 10.1159/000129650 18446019 552. De Castro-Silva C. De Bruin V.M.S. Cunha G.M.A. Nunes D.M. Medeiros C.A.M. De Bruin P.F.C. Melatonin improves sleep and reduces nitrite in the exhaled breath condensate in cystic fibrosis—A randomized, double-blind placebo-controlled study J. Pineal Res. 2010 48 65 71 10.1111/j.1600-079X.2009.00726.x 20025642 553. Moss R.B. Mayer-Hamblett N. Wagener J. Daines C. Hale K. Ahrens R. Gibson R.L. Anderson P. Retsch-Bogart G. Nasr S.Z. Randomized, double-blind, placebo-controlled, dose-escalating study of aerosolized interferon gamma-1b in patients with mild to moderate cystic fibrosis lung disease Pediatr. Pulmonol. 2005 39 209 218 10.1002/ppul.20152 15573395 554. Matsuse T. Teramoto S. Katayama H. Sudo E. Ekimoto H. Mitsuhashi H. Uejima Y. Fukuchi Y. Ouchi Y. ICAM-1 mediates lung leukocyte recruitment but not pulmonary fibrosis in a murine model of bleomycin-induced lung injury Eur. Respir. J. 1999 13 71 77 10.1183/09031936.99.13107199 10836326 555. Ferretti S. Bonneau O. Dubois G.R. Jones C.E. Trifilieff A. IL-17, Produced by Lymphocytes and Neutrophils, Is Necessary for Lipopolysaccharide-Induced Airway Neutrophilia: IL-15 as a Possible Trigger J. Immunol. 2003 170 2106 2112 10.4049/jimmunol.170.4.2106 12574382 556. Ruan H. Pownall H.J. Lodish H.F. Troglitazone antagonizes tumor necrosis factor-α-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-κB J. Biol. Chem. 2003 278 28181 28192 10.1074/jbc.M303141200 12732648 557. Vanden Berghe W. Vermeulen L. Delerive P. De Bosscher K. Staels B. Haegeman G. A paradigm for gene regulation: Inflammation, NF-κB and PPAR Adv. Exp. Med. Biol. 2003 544 181 196 14713228 558. Zingarelli B. Sheehan M. Hake P.W. O’Connor M. Denenberg A. Cook J.A. Peroxisome Proliferator Activator Receptor-γ Ligands, 15-Deoxy-Δ 12,14 -Prostaglandin J 2 and Ciglitazone, Reduce Systemic Inflammation in Polymicrobial Sepsis by Modulation of Signal Transduction Pathways J. Immunol. 2003 171 6827 6837 10.4049/jimmunol.171.12.6827 14662889 559. Perez A. Van Heeckeren A.M. Nichols D. Gupta S. Eastman J.F. Davis P.B. Peroxisome proliferator-activated receptor-γ in cystic fibrosis lung epithelium Am. J. Physiol. Lung Cell. Mol. Physiol. 2008 295 L303 L313 10.1152/ajplung.90276.2008 18556801 560. Dunzendorfer S. Rothbucher D. Schratzberger P. Reinisch N. Kähler C.M. Wiedermann C.J. Mevalonate-dependent inhibition of transendothelial migration and chemotaxis of human peripheral blood neutrophils by pravastatin Circ. Res. 1997 81 963 969 10.1161/01.RES.81.6.963 9400376 561. Rezaie-Majd A. Maca T. Bucek R.A. Valent P. Müller M.R. Husslein P. Kashanipour A. Minar E. Baghestanian M. Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients Arterioscler. Thromb. Vasc. Biol. 2002 22 1194 1199 10.1161/01.ATV.0000022694.16328.CC 12117737 562. Zelvyte I. Dominaitiene R. Crisby M. Janciauskiene S. Modulation of inflammatory mediators and PPARγ and NFκB expression by pravastatin in response to lipoproteins in human monocytes in vitro Pharmacol. Res. 2002 45 147 154 10.1006/phrs.2001.0922 11846628 563. Hopkins N. Gunning Y. O’Croinin D.F. Laffey J.G. McLoughlin P. Anti-inflammatory effect of augmented nitric oxide production in chronic lung infection J. Pathol. 2006 209 198 205 10.1002/path.1963 16538611 564. Watson H. Stackhouse C. Omega-3 fatty acid supplementation for cystic fibrosis Cochrane Database Syst. Rev. 2020 2020 CD002201 10.1002/14651858.CD002201.pub6 565. Lee M. Kim S. Kwon O.K. Oh S.R. Lee H.K. Ahn K. Anti-inflammatory and anti-asthmatic effects of resveratrol, a polyphenolic stilbene, in a mouse model of allergic asthma Int. Immunopharmacol. 2009 9 418 424 10.1016/j.intimp.2009.01.005 19185061 566. Wood L.G. Wark P.A.B. Garg M.L. Antioxidant and anti-inflammatory effects of resveratrol in airway disease Antioxidants Redox Signal. 2010 13 1535 1548 10.1089/ars.2009.3064 567. Georgi E. Le Guellec S. Vecellio L. Fichant E. Stordeur P. Bordeau P. Perraudin J. 68* Feasibility study of OSCN− and lactoferrin (Meveol® ) nebulization for cystic fibrosis patients J. Cyst. Fibros. 2011 10 S18 10.1016/S1569-1993(11)60087-8 568. Chandler J.D. Min E. Huang J. McElroy C.S. Dickerhof N. Mocatta T. Fletcher A.A. Evans C.M. Liang L. Patel M. Antiinflammatory and antimicrobial effects of thiocyanate in a cystic fibrosis mouse model Am. J. Respir. Cell Mol. Biol. 2015 53 193 205 10.1165/rcmb.2014-0208OC 25490247 569. Xiao H. Parkin K.L. Induction of phase II enzyme activity by various selenium compounds Nutr. Cancer 2006 55 210 223 10.1207/s15327914nc5502_13 17044777 570. Galli F. Interactions of Polyphenolic Compounds with Drug Disposition and Metabolism Curr. Drug Metab. 2007 8 830 838 10.2174/138920007782798180 18220564 571. Van Goor F. Hadida S. Grootenhuis P.D.J. Burton B. Cao D. Neuberger T. Turnbull A. Singh A. Joubran J. Hazlewood A. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770 Proc. Natl. Acad. Sci. USA 2009 106 18825 18830 10.1073/pnas.0904709106 19846789