
==== Front
Am J Respir Crit Care Med
Am J Respir Crit Care Med
ajrccm
American Journal of Respiratory and Critical Care Medicine
1073-449X
1535-4970
American Thoracic Society

38820209
202405-0895ED
10.1164/rccm.202405-0895ED
Editorials
Hepatopulmonary Syndrome, Another Face of Dysregulated BMP9 Signaling
https://orcid.org/0000-0002-4913-6713
Sangam Shreya
https://orcid.org/0000-0003-2145-4944
Yu Paul B.
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts
31 5 2024
1 9 2024
31 5 2024
210 5 543544
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).
==== Body
pmcHepatopulmonary syndrome (HPS) is a serious complication of cirrhosis characterized by intrapulmonary vascular dilatation (IPVD), severe hypoxemia, and elevated alveolar–arterial oxygen gradient (A-aO2) (1, 2). Portopulmonary hypertension (PoPH) is another pulmonary vascular complication of liver disease defined by pulmonary arterial hypertension (PAH) caused by the presence of portal hypertension (3). Although both HPS and PoPH stem from abnormal hepatic production or clearance of vasoactive or angiogenic molecules, it remains unclear what factors drive or predict the development of either syndrome. One potential factor, BMP9, a circulating ligand of TGF-β superfamily produced by the liver, is believed to function as an endothelial homeostatic factor (4, 5). BMP9 is known to be reduced in patients with PoPH as well as in those with HPS, and it predicts survival in World Symposium on Pulmonary Hypertension group 1 PAH (6–8). In this context, the mechanistic role of BMP9 in the development of HPS and PoPH warrants further investigation.

In a study reported in this issue of the Journal, Robert and colleagues (pp. 648–661) evaluated the concept that BMP9 deficiency contributes to the development of HPS (9). They examined BMP9 as a potential biomarker of pulmonary vascular disease in a cohort of patients with cirrhosis, including those with HPS, PoPH, or both. Similar to previous findings, the authors found decreased circulating serum BMP9 concentrations in proportion to the severity of cirrhosis (Child–Pugh stage, Model for End-Stage Liver Disease score) (6, 8). In patients with compensated or mild cirrhosis, BMP9 concentrations were lower among those with HPS than those without any pulmonary vascular disease. BMP9 concentrations were equally low in patients with HPS or combined HPS and PoPH, which in turn were lower than those with isolated PoPH, whose BMP9 concentrations were not different from those of patients with cirrhosis without pulmonary vascular disease. In contrast to previous cohorts in which BMP9 concentrations discriminated the presence of PoPH equally or better than HPS (7, 8), BMP9 concentrations appeared to be more sensitive for detecting HPS than isolated PoPH.

To investigate potential mechanisms by which BMP9 might contribute to HPS, the authors used two animal models of portal hypertension: a common bile duct ligation (CBDL) model, previously established as a model of HPS in rats (10), demonstrated diminished hepatic expression of Gdf2 mRNA, circulating BMP9 concentrations, and serum-mediated BMP signaling activity, accompanied by decreased BMP signaling and transcriptional activity in the lungs of rats with HPS. A second model used partial portal vein ligation (PPVL) to reveal features of HPS, including hypoxemia, IPVDs, and increased A-aO2 at 10 weeks. Similar to CBDL rats, PPVL rats had decreased hepatic expression of Gdf2 mRNA, circulating BMP9 concentrations, and serum-mediated BMP signaling, also accompanied by decreased BMP signaling and transcriptional activity in the lungs. These two models support the notion that diminished hepatic BMP9 synthesis and accompanying decreased BMP signaling in lung vasculature are associated with the development of HPS.

Pharmacologic and genetic approaches were taken to demonstrate a causal relationship. BMP signaling was modulated in CBDL and PPVL rats using FK506, a compound that potentiates BMP signaling via interaction with FKBP12, an immunophilin that stabilizes the inactive cytoplasmic kinase domains of BMP type I receptors (11, 12). The administration of FK506 increased the endothelium-specific expression of activated Smad1/5/8 and Id1 in the lungs of CBDL and PPVL rats while reducing manifestations of HPS, including IPVDs, hypoxemia, and A-aO2. Finally, the authors observed that BMP9-deficient (Gdf2−/−) rats spontaneously developed an HPS-like phenotype of intrapulmonary shunting without cirrhosis or portal hypertension. These in vivo studies confirm that impaired BMP9 signaling is sufficient to provoke development of HPS, which could potentially be corrected by augmenting endothelial BMP signaling.

The present findings build on a growing understanding of how BMP9 regulates vascular patterning, how loss-of-function mutations in GDF2 contribute to heritable PAH (13, 14), and how acquired deficiency of BMP9 may not only serve as a biomarker of pulmonary vascular disease associated with cirrhosis but actually drive HPS or PoPH. The present study was unique in defining the presence of HPS, PoPH, or both conditions across the cohort, in contrast to previous studies in which patients with cirrhosis with or without HPS, or with PoPH, were studied as discrete cohorts (7, 8). The composition of the present cohort and the comprehensive phenotyping approach used may have influenced the increased capacity of BMP9 to discriminate HPS versus PoPH compared with previous cohorts.

The CBDL and PPVL models in this study succeed in recapitulating HPS in the context of BMP9 deficiency and portal hypertension but without pulmonary hypertension, whereas the Gdf2−/− rats recapitulate HPS without portal hypertension. Although previous efforts to recapitulate PoPH in animal models have yielded only modest pulmonary hypertension, even with prolonged cirrhosis (6), the robust HPS seen in several models of the present studies suggest HPS may be easier to elicit experimentally. It is widely held that portal hypertension is a critical driver of PoPH and HPS and that attenuating portal hypertension may be effective in the treatment of HPS (15). By demonstrating proof of concept with FK506, this study defines an exciting opportunity to identify novel therapeutics for HPS, including those targeting BMP9 signaling.

Although clinical and translational data in this study shed important new light on the role of BMP9 signaling in pulmonary vascular syndromes associated with liver disease, questions remain. As a biomarker of HPS or PoPH, BMP9 appears more useful among patients with milder cirrhosis, raising the question of why many individuals with severe cirrhosis remain free of either syndrome despite having almost universally diminished BMP9 concentrations. A previous report suggested that BMP10 might be more useful for discriminating HPS than PoPH (7), an observation that would be interesting to test in this well-phenotyped cohort. However, the process of how some patients with cirrhosis develop HPS, PoPH, or both is not likely explained by BMP9 or BMP10 alone but might be attributable to myriad changes in the vasoactive secretome of advanced liver disease. A parallel might be drawn to genetic syndromes of this pathway: loss-of-function mutations in GDF2, and its receptors ACVRL1 and ENG, may give rise to distinct vascular syndromes of PAH or hereditary hemorrhagic telangiectasia, and the determinants may lie in microanatomic and functional diversity of endothelial lineages responsible for distinct forms of vascular remodeling and differential susceptibility of phenotypes to signaling, hemodynamic, inflammatory, genetic, or epigenetic perturbations.

Supported by NIH grants R01AR057374 and R01HL159443.

Originally Published in Press as DOI: 10.1164/rccm.202405-0895ED on May 31, 2024

Author disclosures are available with the text of this article at www.atsjournals.org.
==== Refs
References

1. Rodríguez-Roisin R Krowka MJ Hepatopulmonary syndrome—a liver-induced lung vascular disorder N Engl J Med 2008 358 2378 2387 18509123
2. Fritz JS Fallon MB Kawut SM Pulmonary vascular complications of liver disease Am J Respir Crit Care Med 2013 187 133 143 23155142
3. Le Pavec J Souza R Herve P Lebrec D Savale L Tcherakian C et al. Portopulmonary hypertension: survival and prognostic factors Am J Respir Crit Care Med 2008 178 637 643 18617641
4. David L Mallet C Keramidas M Lamande N Gasc JM Dupuis-Girod S et al. Bone morphogenetic protein-9 is a circulating vascular quiescence factor Circ Res 2008 102 914 922 18309101
5. Miller AF Harvey SA Thies RS Olson MS Bone morphogenetic protein-9: an autocrine/paracrine cytokine in the liver J Biol Chem 2000 275 17937 17945 10849432
6. Nikolic I Yung LM Yang P Malhotra R Paskin-Flerlage SD Dinter T et al. Bone morphogenetic protein 9 is a mechanistic biomarker of portopulmonary hypertension Am J Respir Crit Care Med 2019 199 891 902 30312106
7. Rochon ER Krowka MJ Bartolome S Heresi GA Bull T Roberts K et al. BMP9/10 in pulmonary vascular complications of liver disease Am J Respir Crit Care Med 2020 201 1575 1578 32083953
8. Owen NE Alexander GJ Sen S Bunclark K Polwarth G Pepke-Zaba J et al. Reduced circulating BMP10 and BMP9 and elevated endoglin are associated with disease severity, decompensation and pulmonary vascular syndromes in patients with cirrhosis EBioMedicine 2020 56 102794 32454407
9. Robert F Certain MC Baron A Thuillet R Duhaut L Ottaviani M et al. Disrupted BMP-9 signaling impairs pulmonary vascular integrity in hepatopulmonary syndrome Am J Respir Crit Care Med 2024 210 648 661 38626313
10. Fallon MB Abrams GA McGrath JW Hou Z Luo B Common bile duct ligation in the rat: a model of intrapulmonary vasodilatation and hepatopulmonary syndrome Am J Physiol 1997 272 G779 G784 9142908
11. Wang T Donahoe PK Zervos AS Specific interaction of type I receptors of the TGF-beta family with the immunophilin FKBP-12 Science 1994 265 674 676 7518616
12. Spiekerkoetter E Tian X Cai J Hopper RK Sudheendra D Li CG et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension J Clin Invest 2013 123 3600 3613 23867624
13. Zhu N Pauciulo MW Welch CL Lutz KA Coleman AW Gonzaga-Jauregui C et al. PAH Biobank Enrolling Centers’ Investigators Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension Genome Med 2019 11 69 31727138
14. Gräf S Haimel M Bleda M Hadinnapola C Southgate L Li W et al. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension Nat Commun 2018 9 1416 29650961
15. Raevens S Fallon MB Potential clinical targets in hepatopulmonary syndrome: lessons from experimental models Hepatology 2018 68 2016 2028 29729196
