PMID:16247333

Citation	Sato, N, Kozar, RA, Zou, L, Weatherall, JM, Attuwaybi, B, Moore-Olufemi, SD, Weisbrodt, NW and Moore, FA (2005) Peroxisome proliferator-activated receptor gamma mediates protection against cyclooxygenase-2-induced gut dysfunction in a rodent model of mesenteric ischemia/reperfusion. Shock 24:462-9
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 gamma (PPARgamma) 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 PPARgamma 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 PPARgamma. 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-gamma in shock-induced gut protection.
Links	PubMed
Keywords	Active Transport, Cell Nucleus; Animals; Cell Nucleus/metabolism; Cyclooxygenase 1/metabolism; Cyclooxygenase 2/metabolism; Cyclooxygenase Inhibitors/pharmacology; Cytoplasm/metabolism; Cytosol/metabolism; DNA/chemistry; DNA Primers/chemistry; Dinoprostone/metabolism; Dose-Response Relationship, Drug; Gastrointestinal Tract/pathology; Inflammation; Intestine, Small/pathology; Ischemia/pathology; Male; Mesentery/pathology; Nitrobenzenes/pharmacology; PPAR gamma/metabolism; Peroxidase/metabolism; RNA, Messenger/metabolism; Rats; Rats, Sprague-Dawley; Reperfusion Injury/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides/pharmacology; Time Factors
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:PPARG	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
RAT:PPARG	part_of	GO:0005829: cytosol	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

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