Roles of COX inhibition in pathogenesis of NSAID-induced small intestinal damage.
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin decrease mucosal PGE(2) content by inhibiting cyclooxygenase (COX) activity and produce damage in the small intestine. The development of intestinal lesions 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 SC-560, a selective COX-1 inhibitor, nor rofecoxib, a selective COX-2 inhibitor, alone caused intestinal damage, but their combined administration provoked lesions in the small intestine. SC-560, but not rofecoxib, caused intestinal hypermotility, bacterial invasion and the expression of COX-2 as well as iNOS mRNA, yet the iNOS and MPO activity was increased only when rofecoxib was administered together with SC-560. Although SC-560 inhibited PG production, the level of PGE(2) recovered in a rofecoxib-dependent manner. The intestinal hypermotility in response to indomethacin was prevented by both 16,16-dimethyl PGE(2) and atropine but not by 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, thereby preventing the intestinal damage. 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 the deleterious events caused by COX-1 inhibition and maintains mucosal integrity. These sequences of events explain why intestinal damage occurs when both COX-1 and COX-2 are inhibited.
Takeuchi
Koji
K
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Japan. takeuchi@mb.kyoto-phu.ac.jp
Tanaka
Akiko
A
Kato
Shinichi
S
Amagase
Kikuko
K
Satoh
Hiroshi
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects / Q000494:pharmacology; D007421:Intestine, Small / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D007783:Lactones / Q000009:adverse effects / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology; D013450:Sulfones / Q000009:adverse effects / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D011720:Pyrazoles; C115461:SC 560; D013450:Sulfones; C116926:rofecoxib; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin