title: 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.
  
  
  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.affiliation: Department of Anesthesia and Intensive Care Medicine, Royal College of Surgeons of Ireland, Beaumont Hospital Dublin, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Scully
authors.forename: Chen
authors.initials: C
authors.lastname: Gang
authors.forename: Claire
authors.initials: C
authors.lastname: Condron
authors.forename: David
authors.initials: D
authors.lastname: Bouchier-Hayes
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D016285:Iloprost / Q000494:pharmacology; D044045:Lipoxins / Q000378:metabolism*; D008168:Lung / Q000187:drug effects*; D055370:Lung Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D020011:Protective Agents / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D001241:Aspirin; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016285:Iloprost; D044045:Lipoxins; D020011:Protective Agents; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C040527:lipoxin A4