title: Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury.
abstract: Acute lung injury (ALI) is a severe illness with excess mortality and no specific therapy. In its early exudative phase, neutrophil activation and accumulation in the lung lead to hypoxemia, widespread tissue damage, and respiratory failure. In clinical trials, inhibition of proinflammatory mediators has not proven effective. In this study, we pursued a new investigative strategy that emphasizes mediators promoting resolution from lung injury. A new spontaneously resolving experimental murine model of ALI from acid aspiration was developed to identify endogenous proresolving mechanisms. ALI increased cyclooxygenase 2 (COX-2) expression in murine lung. Selective pharmacologic inhibition or gene disruption of COX-2 blocked resolution of ALI. COX-2-derived products increased levels of the proresolving lipid mediators lipoxin A4 (LXA4) and, in the presence of aspirin, 15-epi-LXA4. Both LXA4 and 15-epi-LXA4 interact with the LXA4 receptor (ALX) to mediate anti-inflammatory actions. ALX expression was markedly induced by acid injury and transgenic mice with increased ALX expression displayed dramatic protection from ALI. Together, these findings indicate a protective role in ALI for COX-2-derived mediators, in part via enhanced lipoxin signaling, and carry potential therapeutic implications for this devastating clinical disorder.
authors.affiliation: Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Payal
authors.initials: P
authors.lastname: Kohli
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonnans
authors.forename: Laura E
authors.initials: LE
authors.lastname: Fredenburgh
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Levy
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D006851:Hydrochloric Acid / Q000633:toxicity; D018836:Inflammation Mediators / Q000378:metabolism; D044045:Lipoxins / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D055370:Lung Injury; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D018076:DNA, Complementary; C105101:FPR2 protein, human; D018836:Inflammation Mediators; D044045:Lipoxins; D008565:Membrane Proteins; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C040527:lipoxin A4; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D006851:Hydrochloric Acid