Increased susceptibility of small intestine to NSAID-provoked ulceration in rats with adjuvant-induced arthritis: involvement of enhanced expression of TLR4.

NSAIDs damage the small intestine as well as the stomach as adverse effects. We previously reported that the gastric ulcerogenic response to NSAIDs was markedly increased in arthritic rats. The present study was designed to examine the intestinal ulcerogenic property of indomethacin in adjuvant-induced arthritic rats in comparison with normal animals. Arthritis was induced in male Dark Agouti rats by injection of Freund's complete adjuvant into the right hindfoot. Two weeks later, indomethacin was given orally and the intestine was examined for lesions at several time points after indomethacin. Indomethacin produced intestinal lesions in both normal and arthritic rats, but in the latter, the ulcerogenic response occurred much earlier and the severity was markedly enhanced. Aminoguanidine, an inhibitor of iNOS, significantly suppressed the damage, yet the efficacy differed in normal and arthritic rats, depending on the dose schedule; the effect of post-administration (6 h after) was greater than that of pre-administration (0.5 h before) in normal rats, whereas that of post-administration was less than that of pre-administration in arthritic rats. The expression of iNOS and TLR4 in the intestine was enhanced in arthritic rats as compared with normal rats. These results suggest that the intestinal ulcerogenic response to indomethacin is markedly aggravated in arthritic rats. Notably, the onset of the ulceration was much earlier in arthritic rats than normal rats. These phenomena may be accounted for by the upregulation of iNOS/NO through the increased expression of TLR4 in the small intestine of arthritic rats.