Role of COX inhibition in pathogenesis of NSAID-induced small intestinal damage.
Nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin decrease mucosal PGE(2) production by inhibiting cyclooxygenase (COX) activity and produce damage in the small intestine. The development of intestinal lesions as induced by indomethacin was accompanied by increases in intestinal motility, enterobacterial invasion, and myeloperoxidase (MPO) as well as inducible nitric oxide synthase (iNOS) activity, together with the up-regulation of COX-2 and iNOS mRNA expression. Neither the selective COX-1 inhibitor, SC-560, nor the selective COX-2 inhibitor, rofecoxib, alone caused intestinal damage, but their combined administration produced lesions. SC-560, but not rofecoxib, caused intestinal hypermotility, bacterial invasion and the expression of COX-2 as well as iNOS mRNAs, yet the iNOS and MPO activity was increased only when rofecoxib was administered together with SC-560. Although SC-560 inhibited the PG production, the level of PGE(2) was recovered, in a rofecoxib-dependent manner. The intestinal hypermotility response to indomethacin was prevented by both 16,16-dimethyl PGE(2) and atropine but not ampicillin, yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 as well as the iNOS activity in the intestinal mucosa following indomethacin treatment, resulting in preventing the intestinal lesions. These results suggest that inhibition of COX-1, despite causing intestinal hypermotility, bacterial invasion and iNOS expression, up-regulates the expression of COX-2, and the PGE(2) derived from COX-2 counteracts deleterious events caused by COX-1 inhibition and maintains the mucosal integrity. These sequences of events explain why intestinal damage occurs when both COX-1 and COX-2 are inhibited.
Takeuchi
K
K
Department of Pharmacology and Experimental Therapeutics Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan. takeuchi@mb.kyoto-phu.ac.jp
Tanaka
A
A
Ohno
R
R
Yokota
A
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases