Roles of enterobacteria, nitric oxide and neutrophil in pathogenesis of indomethacin-induced small intestinal lesions in rats

Roles of enterobacteria, nitric oxide (NO) and neutrophil in indomethacin-i nduced small intestinal lesions were examined in rats. Indomethacin (10 mg kg(-1)), administered s.c. as a single injection, caused haemorrhagic lesio ns in the small intestine, mostly in the jejunum and ileum. The lesions wer e first observed 6 h after administration of indomethacin, the severity inc reasing progressively with time up to 24 h later. Following indomethacin, t he enterobacterial numbers, inducible NO synthase (iNOS) activity and NO pr oduction in the intestinal mucosa were also increased with time, and change s in the former preceded those in the latter two as well as the occurrence of intestinal damage. Treatment of the animals with both N-G-nitro-L-argini ne methyl ester (L-NAME) and aminoguanidine prevented intestinal lesions in duced by indomethacin, with suppression of NO production. Both dexamethason e and FR167653 (an inhibitor of interleukin-1 beta/tumour necrosis factor-a lpha production) also reduced the severity of intestinal lesions as well as the increase in NOS activity following administration of indomethacin. Lik ewise, the occurrence of intestinal lesions was attenuated by pretreatment of the animals with anti-neutrophil serum (ANS). None of these treatments, however, affect the translocation of enterobacteria in the mucosa. By contr ast, ampicillin (an anti-bacterial agent) suppressed the increase in mucosa l iNOS activity as well as the enterobacterial numbers invaded in the mucos a and inhibited the occurrence of intestinal lesions after administration o f indomethacin. These results strongly suggest that enterobacterial translo cation in the mucosa is the first step required for activation of various f actors such as iNOS/NO and neutrophils, all involved in the pathogenesis of indomethacin-induced intestinal lesions. (C) 1999 Academic Press.