PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ?? MEDIATES PROTECTION AGAINST CYCLOOXYGENASE-2-INDUCED GUT DYSFUNCTION IN A RODENT MODEL OF MESENTERIC ISCHEMIA/REPERFUSION

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Abstract
Cyclooxygenase (COX)-2 has been identified as an important mediator elaborated during ischemia/reperfusion, with pro- and anti-inflammatory properties having been reported. As the role of COX-2 in the small intestine remains unclear, we hypothesized that COX-2 expression would mediate mesenteric ischemia/reperfusion-induced gut injury, inflammation, and impaired transit and that these deleterious effects could be reversed by the selective COX-2 inhibitor, N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulphanamide (NS-398). Additionally, we sought to determine the role of peroxisome proliferator-activated receptor γ (PPARγ) in mediating protection by NS-398 in this model. Rats underwent sham surgery or were pretreated with NS-398 (3, 10, or 30 mg/kg) intraperitoneally 1 h before 60 min of superior mesenteric artery occlusion and 30 min to 6 h of reperfusion. In some experiments, NS-398 (30 mg/kg) was administered postischemia. Ileum was harvested for COX-2 mRNA and protein, PGE2, myeloperoxidase (inflammation), histology (injury), intestinal transit and PPARγ protein expression, and DNA-binding activity. COX-2 expression and PGE2 production increased after mesenteric ischemia/reperfusion and were associated with gut inflammation, injury, and impaired transit. Inhibition of COX-2 by NS-398 (30 mg/kg, but not 3 or 10 mg/kg) not only reversed the deleterious effects of COX-2, but additionally induced expression and nuclear translocation of PPARγ. NS-398 given postischemia was equally protective. In conclusion, COX-2 may function as a proinflammatory mediator in a rodent model of mesenteric ischemia/reperfusion. Reversal of gut inflammation, injury, and impaired transit by high-dose NS-398 is associated with PPAR activation, suggesting a potential role for PPAR-γ in shock-induced gut protection.