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 |
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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 |
format | Article |
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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.</description><identifier>ISSN: 0009-8981</identifier><identifier>EISSN: 1873-3492</identifier><identifier>DOI: 10.1016/j.cca.2009.12.026</identifier><identifier>PMID: 20074562</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>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</subject><ispartof>Clinica chimica acta, 2010-04, Vol.411 (7), p.459-466</ispartof><rights>2010 Elsevier B.V.</rights><rights>2010 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-3e5a32a6166d313880bb81332cee470c0e6e3e90dd4a114f66b521512c53e3d03</citedby><cites>FETCH-LOGICAL-c418t-3e5a32a6166d313880bb81332cee470c0e6e3e90dd4a114f66b521512c53e3d03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.cca.2009.12.026$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20074562$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Takeuchi, Koji</creatorcontrib><creatorcontrib>Tanaka, Akiko</creatorcontrib><creatorcontrib>Kato, Shinichi</creatorcontrib><creatorcontrib>Amagase, Kikuko</creatorcontrib><creatorcontrib>Satoh, Hiroshi</creatorcontrib><title>Roles of COX inhibition in pathogenesis of NSAID-induced small intestinal damage</title><title>Clinica chimica acta</title><addtitle>Clin Chim Acta</addtitle><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.</description><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - adverse effects</subject><subject>COX-1 inhibition</subject><subject>COX-2 inhibition</subject><subject>Cyclooxygenase Inhibitors - adverse effects</subject><subject>Humans</subject><subject>Indomethacin - adverse effects</subject><subject>Indomethacin - pharmacology</subject><subject>Intestinal damage</subject><subject>Intestine, Small - drug effects</subject><subject>Intestine, Small - enzymology</subject><subject>Intestine, Small - pathology</subject><subject>Lactones - adverse effects</subject><subject>Lactones - pharmacology</subject><subject>NSAID</subject><subject>Pathogenic mechanism</subject><subject>Prostaglandin-Endoperoxide Synthases - metabolism</subject><subject>Pyrazoles - adverse effects</subject><subject>Pyrazoles - pharmacology</subject><subject>Sulfones - adverse effects</subject><subject>Sulfones - pharmacology</subject><issn>0009-8981</issn><issn>1873-3492</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtOwzAQRS0EoqXwAWxQdqwSPLbjJmJVlVeliiIeEjvLsaetqzxKnCLx97i0sGTlsebcK_sQcg40AQryapUYoxNGaZ4ASyiTB6QP2ZDHXOTskPRp2MRZnkGPnHi_CldBJRyTXogMRSpZnzw9NyX6qJlH49l75OqlK1znmjqM0Vp3y2aBNXr3Qzy-jCY3savtxqCNfKXLMmAd-s7VuoysrvQCT8nRXJcez_bngLzd3b6OH-Lp7H4yHk1jIyDrYo6p5kxLkNJy4FlGiyIDzplBFENqKErkmFNrhQYQcymLlEEKzKQcuaV8QC53veu2-diEN6jKeYNlqWtsNl4NOc9TIaQMJOxI0zbetzhX69ZVuv1SQNXWo1qp4FFtPSpgKngMmYt9-6ao0P4lfsUF4HoHYPjjp8NWeeOwDmJci6ZTtnH_1H8DLNOBUw</recordid><startdate>20100402</startdate><enddate>20100402</enddate><creator>Takeuchi, Koji</creator><creator>Tanaka, Akiko</creator><creator>Kato, Shinichi</creator><creator>Amagase, Kikuko</creator><creator>Satoh, Hiroshi</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20100402</creationdate><title>Roles of COX inhibition in pathogenesis of NSAID-induced small intestinal damage</title><author>Takeuchi, Koji ; Tanaka, Akiko ; Kato, Shinichi ; Amagase, Kikuko ; Satoh, Hiroshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-3e5a32a6166d313880bb81332cee470c0e6e3e90dd4a114f66b521512c53e3d03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - adverse effects</topic><topic>COX-1 inhibition</topic><topic>COX-2 inhibition</topic><topic>Cyclooxygenase Inhibitors - adverse effects</topic><topic>Humans</topic><topic>Indomethacin - adverse effects</topic><topic>Indomethacin - pharmacology</topic><topic>Intestinal damage</topic><topic>Intestine, Small - drug effects</topic><topic>Intestine, Small - enzymology</topic><topic>Intestine, Small - pathology</topic><topic>Lactones - adverse effects</topic><topic>Lactones - pharmacology</topic><topic>NSAID</topic><topic>Pathogenic mechanism</topic><topic>Prostaglandin-Endoperoxide Synthases - metabolism</topic><topic>Pyrazoles - adverse effects</topic><topic>Pyrazoles - pharmacology</topic><topic>Sulfones - adverse effects</topic><topic>Sulfones - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takeuchi, Koji</creatorcontrib><creatorcontrib>Tanaka, Akiko</creatorcontrib><creatorcontrib>Kato, Shinichi</creatorcontrib><creatorcontrib>Amagase, Kikuko</creatorcontrib><creatorcontrib>Satoh, Hiroshi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinica chimica acta</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Takeuchi, Koji</au><au>Tanaka, Akiko</au><au>Kato, Shinichi</au><au>Amagase, Kikuko</au><au>Satoh, Hiroshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Roles of COX inhibition in pathogenesis of NSAID-induced small intestinal damage</atitle><jtitle>Clinica chimica acta</jtitle><addtitle>Clin Chim Acta</addtitle><date>2010-04-02</date><risdate>2010</risdate><volume>411</volume><issue>7</issue><spage>459</spage><epage>466</epage><pages>459-466</pages><issn>0009-8981</issn><eissn>1873-3492</eissn><abstract>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.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>20074562</pmid><doi>10.1016/j.cca.2009.12.026</doi><tpages>8</tpages></addata></record> |
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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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