Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury

Koichi Fukunaga, Payal Kohli, Caroline Bonnans, Laura E. Fredenburgh, Bruce D. Levy

Research output: Contribution to journalArticle

213 Citations (Scopus)

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 A 4 (LXA4) and, in the presence of aspirin, 15-epi-LXA 4. 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.

Original languageEnglish
Pages (from-to)5033-5039
Number of pages7
JournalJournal of Immunology
Volume174
Issue number8
DOIs
Publication statusPublished - 2005 Apr 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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