Roles of enterobacteria,
nitric oxide (NO) and neutrophil in
indomethacin-induced small intestinal lesions were examined in rats.
Indomethacin (10 mg kg-1), administered s.c. as a single injection, caused haemorrhagic lesions in the small intestine, mostly in the jejunum and ileum. The lesions were first observed 6 h after administration of
indomethacin, the severity increasing progressively with time up to 24 h later. Following
indomethacin, the enterobacterial numbers, inducible
NO synthase (iNOS) activity and NO production in the intestinal mucosa were also increased with time, and changes in the former preceded those in the latter two as well as the occurrence of intestinal damage. Treatment of the animals with both
NG-nitro-L-arginine methyl ester (
L-NAME) and
aminoguanidine prevented intestinal lesions induced by
indomethacin, with suppression of NO production. Both
dexamethasone and
FR167653 (an inhibitor of
interleukin-1 beta/tumour
necrosis factor-alpha production) also reduced the severity of intestinal lesions as well as the increase in iNOS activity following administration of
indomethacin. Likewise, 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 contrast,
ampicillin (an
anti-bacterial agent) suppressed the increase in mucosal iNOS activity as well as the enterobacterial numbers invaded in the mucosa and inhibited the occurrence of intestinal lesions after administration of
indomethacin. These results strongly suggest that enterobacterial translocation in the mucosa is the first step required for activation of various factors such as iNOS/NO and neutrophils, all involved in the pathogenesis of
indomethacin-induced intestinal lesions.