Protective Role of Cyclooxygenase (COX)-2 in Experimental Lung Injury: Evidence of a Lipoxin A4-Mediated Effect1

BackgroundPolymorphoneutrophils (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 A4 in experimental I/R-mediated lung injury.Materials and MethodsSprague-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 (PGI2) analogue. Lung injury was assessed by wet/dry ratio, myeloperoxidase (MPO) activity, and bronchoalveolar lavage (BAL) neutrophil counts. BAL levels of thromboxane, PGE2, 6-keto-PGF1α (a hydrolysis product of prostacyclin), lipoxin A4, and 15-epi-lipoxin A4 were analyzed by enzyme immunoassay (EIA). Immunostaining for COX-2 was performed.ResultsI/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 PGE2 and 6-keto-PGF1α levels in BAL. SC236 markedly reduced these prostanoids and lipoxin A4 compared with I/R alone. Iloprost markedly increased lipoxin A4 levels. The deleterious effect of SC236 and the beneficial effect of iloprost was associated with a reduction and an increase, respectively, in lipoxin A4 levels.ConclusionsLipoxin A4 warrants further evaluation as a mediator of COX-2 regulated lung protection.