PT  - JOURNAL ARTICLE
AU  - Jun Katada
AU  - Hitomi Saito
AU  - Akira Ohashi
TI  - Significance of Cyclooxygenase-2 Induced via p38 Mitogen-Activated Protein Kinase in Mechanical Stimulus-Induced Peritoneal Adhesion in Mice
AID  - 10.1124/jpet.104.078717
DP  - 2005 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 286--292
VI  - 313
IP  - 1
4099  - http://jpet.aspetjournals.org/content/313/1/286.short
4100  - http://jpet.aspetjournals.org/content/313/1/286.full
SO  - J Pharmacol Exp Ther2005 Apr 01; 313
AB  - Postoperative peritoneal adhesion represents a major complication of surgery, but the molecular mechanism underlying pathogenesis of adhesion is not fully understood. The present study investigated the roles of cyclooxygenase (COX)-1 and COX-2 in peritoneal adhesion induced by scraping the surface of the cecum and abdominal wall in mice. Slight, but macroscopically observable, peritoneal adhesion was induced even on day 1, and the extent of adhesion reached a maximum on day 7 and beyond. COX-1 mRNA was constitutively expressed in the intact cecum, and its expression level was not altered after the mechanical stimulus. In contrast, expression of the COX-2 gene was markedly increased after the stimulus, and maximum expression was observed on days 3 to 7. Mofezolac, a specific COX-1 inhibitor, had no effect on peritoneal adhesion at 30 mg/kg and had only marginal effects on prostaglandin (PG)E2 levels in the cecum or peritoneal fluid. On the other hand, two highly selective inhibitors for COX-2, NS-398 (N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide) and CAY10404 [3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole], dose-dependently inhibited both adhesion formation and the increase in PGE2 levels (3-30 mg/kg). The effects of NS-398 were eliminated when PGE2 or (R)-butaprost was administered exogenously. A COX-2 antisense oligonucleotide also attenuated adhesion formation. Activation of p38 mitogen-activated protein (MAP) kinase was observed in the traumatized cecum, and an MAP kinase inhibitor, SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole], inhibited adhesion formation (54% inhibition at 15 μM) and also reduced the COX-2 mRNA level and PGE2 levels. In conclusion, COX-2, but not COX-1, plays a significant role in mechanical stimulus-induced peritoneal formation in the mouse cecum. The American Society for Pharmacology and Experimental Therapeutics