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Vol. 303, Issue 3, 1248-1254, December 2002
Department of Pharmacology and Experimental Therapeutics, Kyoto
Pharmaceutical University, Kyoto, Japan
We recently reported that cyclooxygenase (COX)-2 expression was
up-regulated in the rat small intestine after administration of
indomethacin, and this may be a key to nonsteroidal anti-inflammatory drug (NSAID)-induced intestinal damage. In the present study, we
investigated the effect of inhibiting COX-1 or COX-2 on various intestinal events occurring in association with NSAID-induced intestinal damage. Rats without fasting were treated with indomethacin, SC-560 (a selective COX-1 inhibitor), rofecoxib (a selective COX-2 inhibitor), or SC-560 plus rofecoxib, and the following parameters were
examined in the small intestine: the lesion score, the enterobacterial number, myeloperoxidase (MPO) and inducible nitric-oxide synthase (iNOS) activity, and intestinal motility. Indomethacin decreased mucosal prostaglandin (PG)E2 content and caused damage in
the intestine within 24 h, accompanied by an increase in
intestinal contractility, bacterial numbers, and MPO as well as iNOS
activity, together with the up-regulation of COX-2 and iNOS mRNA
expression. Neither SC-560 nor rofecoxib alone caused intestinal
damage, but their combined administration produced lesions. SC-560, but
not rofecoxib, caused intestinal hypermotility, bacterial invasion, and
COX-2 as well as iNOS mRNA expression, yet the iNOS and MPO activity
was increased only when rofecoxib was also administered. Although
SC-560 inhibited the PG production, the level of PGE2 was
restored 6 h later, in a rofecoxib-dependent manner. We conclude that inhibition of COX-1, despite causing intestinal hypermotility, bacterial invasion, and iNOS expression, up-regulates the expression of
COX-2, and the PGE2 produced by COX-2 counteracts
deleterious events, and maintains the mucosal integrity. This sequence
of events explains why intestinal damage occurs only when both COX-1 and COX-2 are inhibited.
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