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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Role of Cyclooxygenase (COX)-1 and COX-2 Inhibition in Nonsteroidal Anti-Inflammatory Drug-Induced Intestinal Damage in Rats: Relation to Various Pathogenic Events

Akiko Tanaka, Shoko Hase, Tohru Miyazawa, Ryoko Ohno and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics December 2002, 303 (3) 1248-1254; DOI: https://doi.org/10.1124/jpet.102.041715
Akiko Tanaka
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
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Shoko Hase
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
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Tohru Miyazawa
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
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Ryoko Ohno
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
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Koji Takeuchi
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
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Abstract

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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Journal of Pharmacology and Experimental Therapeutics: 303 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 3
1 Dec 2002
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Role of Cyclooxygenase (COX)-1 and COX-2 Inhibition in Nonsteroidal Anti-Inflammatory Drug-Induced Intestinal Damage in Rats: Relation to Various Pathogenic Events

Akiko Tanaka, Shoko Hase, Tohru Miyazawa, Ryoko Ohno and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics December 1, 2002, 303 (3) 1248-1254; DOI: https://doi.org/10.1124/jpet.102.041715

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Role of Cyclooxygenase (COX)-1 and COX-2 Inhibition in Nonsteroidal Anti-Inflammatory Drug-Induced Intestinal Damage in Rats: Relation to Various Pathogenic Events

Akiko Tanaka, Shoko Hase, Tohru Miyazawa, Ryoko Ohno and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics December 1, 2002, 303 (3) 1248-1254; DOI: https://doi.org/10.1124/jpet.102.041715
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