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,...

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Veröffentlicht in:Clinica chimica acta 2010-04, Vol.411 (7), p.459-466
Hauptverfasser: Takeuchi, Koji, Tanaka, Akiko, Kato, Shinichi, Amagase, Kikuko, Satoh, Hiroshi
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container_issue 7
container_start_page 459
container_title Clinica chimica acta
container_volume 411
creator Takeuchi, Koji
Tanaka, Akiko
Kato, Shinichi
Amagase, Kikuko
Satoh, Hiroshi
description 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.
doi_str_mv 10.1016/j.cca.2009.12.026
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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. 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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. 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subjects Animals
Anti-Inflammatory Agents, Non-Steroidal - adverse effects
COX-1 inhibition
COX-2 inhibition
Cyclooxygenase Inhibitors - adverse effects
Humans
Indomethacin - adverse effects
Indomethacin - pharmacology
Intestinal damage
Intestine, Small - drug effects
Intestine, Small - enzymology
Intestine, Small - pathology
Lactones - adverse effects
Lactones - pharmacology
NSAID
Pathogenic mechanism
Prostaglandin-Endoperoxide Synthases - metabolism
Pyrazoles - adverse effects
Pyrazoles - pharmacology
Sulfones - adverse effects
Sulfones - pharmacology
title Roles of COX inhibition in pathogenesis of NSAID-induced small intestinal damage
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