thromboxane-a2 and Colitis

Neutrophil elastase (NE) is a factor that aggravates colitis. We investigated the influence of thromboxane A2 (TXA2) and leukotriene B4 (LTB4) on NE release in Syrian hamsters with trinitrobenzene sulfonic acid-induced colitis. Colonic specimens with colitis were incubated with U-46619 (a TXA2 analogue) or LTB4 in vitro and NE release was examined. As a result, U-46619 increased NE release, while LTB4 had no effect. The NE release induced by U-46619 was inhibited by a TP-receptor antagonist. To demonstrate that TXA2 caused NE release in vivo as well, while LTB4 did not, colitis animals were treated with nordihydroguaiaretic acid (NDGA), a dual inhibitor of cyclooxygenase/lipoxygenase; and colonic luminal TXB(A)2 and LTB4 levels and NE activity were determined. The TXB(A)2 level was significantly correlated with NE activity, while no correlation was found between LTB4 and NE activity. An inhibitory effect of NDGA on the ulcer area was also observed, and NE activity was significantly correlated with the ulcer area. The suppression of TXA2 production by NDGA may result in the inhibition of NE release so that colonic tissue damage becomes less severe. Regulation of NE release is a new biological action of TXA2 that has not been reported before.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Colitis; Cricetinae; Disease Models, Animal; Leukocyte Elastase; Leukotriene B4; Male; Mesocricetus; Specific Pathogen-Free Organisms; Thromboxane A2; Trinitrobenzenesulfonic Acid; Up-Regulation

We evaluated the effects of an antagonist of the thromboxane A2 receptor (ONO-NT-126) in an animal model of inflammatory bowel disease (IBD).. Colitis was induced by intracolonic instillation of trinitrobenzenesulfonic acid/ethanol in male Wistar rats. ONO-NT-126 or vehicle alone was administered intraluminally via anus once a day. The rats were killed after 7 days for assessment of colonic damage by the colonic damage score.. ONO-NT-126 markedly reduced the colonic damage. Our findings suggest that the thromboxane-thromboxane receptor system plays an important role in this model of IBD and that antagonism of the thromboxane A2 receptor may prove useful for the treatment of IBD.

Topics: Animals; Bridged Bicyclo Compounds; Colitis; Colon; Dose-Response Relationship, Drug; Ethanol; Fatty Acids, Monounsaturated; Leukotriene B4; Male; Rats; Rats, Wistar; Receptors, Thromboxane; Thromboxane A2; Trinitrobenzenesulfonic Acid