Protective role of cyclooxygenase (COX)-2 in experimental lung injury: evidence of a lipoxin A4-mediated effect.

Abstract

BACKGROUND:

Polymorphoneutrophils (PMNs) are activated by inflammatory mediators following splanchnic ischemia/reperfusion (I/R), potentially injuring organs such as the lung. As a result, some patients develop respiratory failure following abdominal aortic aneurysm repair. Pulmonary cyclooxygenase (COX)-2 protects against acid aspiration and bacterial instillation via lipoxins, a family of potent anti-inflammatory lipid mediators. We explored the role of COX-2 and lipoxin A(4) in experimental I/R-mediated lung injury.

MATERIALS AND METHODS:

Sprague-Dawley rats were assigned to one of the following five groups: (1) controls; (2) aortic cross-clamping for 45 min and reperfusion for 4 h (I/R group); (3) I/R and SC236, a selective COX-2 inhibitor; (4) I/R and aspirin; and (5) I/R and iloprost, a prostacyclin (PGI(2)) analogue. Lung injury was assessed by wet/dry ratio, myeloperoxidase (MPO) activity, and bronchoalveolar lavage (BAL) neutrophil counts. BAL levels of thromboxane, PGE(2), 6-keto-PGF(1)α (a hydrolysis product of prostacyclin), lipoxin A(4), and 15-epi-lipoxin A(4) were analyzed by enzyme immunoassay (EIA). Immunostaining for COX-2 was performed.

RESULTS:

I/R significantly increased tissue MPO, the wet/dry lung ratio, and neutrophil counts. These measures were significantly further aggravated by SC236 and improved by iloprost. I/R increased COX-2 immunostaining and both PGE(2) and 6-keto-PGF(1α) levels in BAL. SC236 markedly reduced these prostanoids and lipoxin A(4) compared with I/R alone. Iloprost markedly increased lipoxin A(4) levels. The deleterious effect of SC236 and the beneficial effect of iloprost was associated with a reduction and an increase, respectively, in lipoxin A(4) levels.

CONCLUSIONS:

Lipoxin A(4) warrants further evaluation as a mediator of COX-2 regulated lung protection.

• Authors: Michael Scully, Chen Gang, Claire Condron, David Bouchier-Hayes, Anthony J Cunningham
• Journal: The Journal of surgical research (J Surg Res) Vol. 175 Issue 1 Pg. 176-84 (Jun 01 2012) ISSN: 1095-8673 [Electronic] United States
• PMID: 21944479 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012. Published by Elsevier Inc.

Chemical References

• 4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
• Cyclooxygenase 2 Inhibitors
• Lipoxins
• Protective Agents
• Pyrazoles
• Sulfonamides
• lipoxin A4
• Cyclooxygenase 2
• Iloprost
• Aspirin

Topics

• Animals
• Aspirin (pharmacology)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Disease Models, Animal
• Iloprost (pharmacology)
• Lipoxins (metabolism)
• Lung (drug effects)
• Lung Injury (metabolism, physiopathology, prevention & control)
• Male
• Protective Agents (pharmacology)
• Pyrazoles (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (metabolism, physiopathology, prevention & control)
• Sulfonamides (pharmacology)