PMID- 10430612
OWN - NLM
STAT- MEDLINE
DCOM- 19990817
LR  - 20181113
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 104
IP  - 3
DP  - 1999 Aug
TI  - Leukotriene B4 receptor transgenic mice reveal novel protective roles for
      lipoxins and aspirin-triggered lipoxins in reperfusion.
PG  - 309-16
AB  - Polymorphonuclear neutrophil (PMN) activation is pivotal in acute inflammation
      and injury from reperfusion. To elucidate components controlling PMNs in vivo, we
      prepared novel transgenic mice with the human leukotriene (LT) B4 receptor (BLTR)
      for functional characterization. Overexpression of BLTR in leukocytes
      dramatically increased PMN trafficking to skin microabscesses and lungs after
      ischemia-reperfusion, whereas mice deficient in 5-lipoxygenase (5-LO) showed
      diminished PMN accumulation in reperfused lungs. Hence, both BLTR expression and 
      LT biosynthesis are critical for PMN infiltration in reperfusion-initiated
      second-organ injury. Also, in BLTR transgenic mice, 5-LO expression and product
      formation were selectively increased in exudates, demonstrating that receptor
      overexpression amplifies proinflammatory circuits. Endogenous lipoxin (LX) A4 was
      produced in ischemic lungs and elevated by reperfusion. Because LXA4 and
      aspirin-triggered 15-epimeric LXA4 (ATL) selectively regulate leukocyte
      responses, they were tested in BLTR transgenic mice. Despite excessive PMN
      recruitment in BLTR transgenic mice, intravenous injection of ATL sharply
      diminished reperfusion-initiated PMN trafficking to remote organs, and topical
      application of LX was protective in acute dermal inflammation. These results
      demonstrate a direct role for BLTR with positive feedback, involving BLTR and
      5-LO signaling in controlling PMNs. Moreover, LXA4 and ATL counter BLTR-amplified
      networks, revealing a novel protective role for LX and ATL in stress responses
      that has applications in perioperative medicine.
FAU - Chiang, N
AU  - Chiang N
AD  - Center for Experimental Therapeutics and Reperfusion Injury, Department of
      Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital,
      Boston, Massachusetts 02115, USA.
FAU - Gronert, K
AU  - Gronert K
FAU - Clish, C B
AU  - Clish CB
FAU - O'Brien, J A
AU  - O'Brien JA
FAU - Freeman, M W
AU  - Freeman MW
FAU - Serhan, C N
AU  - Serhan CN
LA  - eng
GR  - R01 GM038765/GM/NIGMS NIH HHS/United States
GR  - P01 DK050305/DK/NIDDK NIH HHS/United States
GR  - R37 GM038765/GM/NIGMS NIH HHS/United States
GR  - DK-50305/DK/NIDDK NIH HHS/United States
GR  - GM-38765/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (FPR2 protein, human)
RN  - 0 (Hydroxyeicosatetraenoic Acids)
RN  - 0 (Lipoxins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Receptors, Formyl Peptide)
RN  - 0 (Receptors, Leukotriene B4)
RN  - 0 (Receptors, Lipoxin)
RN  - 0 (lipoxin A4)
RN  - EC 1.13.11.34 (Arachidonate 5-Lipoxygenase)
RN  - R16CO5Y76E (Aspirin)
SB  - AIM
SB  - IM
MH  - Animals
MH  - Arachidonate 5-Lipoxygenase/deficiency/genetics
MH  - Aspirin/*pharmacology
MH  - Cell Line
MH  - Cell Movement
MH  - Crosses, Genetic
MH  - Ear, External
MH  - Exudates and Transudates
MH  - Female
MH  - HL-60 Cells
MH  - Hindlimb
MH  - Humans
MH  - Hydroxyeicosatetraenoic Acids/biosynthesis/*physiology
MH  - *Lipoxins
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Neutrophils/pathology
MH  - Peritonitis/metabolism/pathology
MH  - RNA, Messenger/biosynthesis
MH  - Receptors, Cell Surface/*physiology
MH  - *Receptors, Formyl Peptide
MH  - Receptors, Leukotriene B4/biosynthesis/*genetics/physiology
MH  - *Receptors, Lipoxin
MH  - Reperfusion Injury/genetics/*metabolism/pathology
PMC - PMC408424
EDAT- 1999/08/03 00:00
MHDA- 1999/08/03 00:01
CRDT- 1999/08/03 00:00
PHST- 1999/08/03 00:00 [pubmed]
PHST- 1999/08/03 00:01 [medline]
PHST- 1999/08/03 00:00 [entrez]
AID - 10.1172/JCI7016 [doi]
PST - ppublish
SO  - J Clin Invest. 1999 Aug;104(3):309-16. doi: 10.1172/JCI7016.