Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II
PROSTAGLANDINS have wide-ranging effects in the body and are thought to be important mediators of inflammation. Cyclooxygen-ase (COX) plays a key regulatory role in prostaglandin synthesis, and occurs in both constitutive (COX-1) and inducible (COX-2) isoforms 1,2 . COX-1 is thought to provide cytop...
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| Veröffentlicht in: | Nature (London) 1995-11, Vol.378 (6555), p.406-409 |
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| creator | Dinchuk, Joseph E. Car, Bruce D. Focht, Richard J. Johnston, Jennifer J. Jaffee, Bruce D. Covington, Maryanne B. Contel, Nancy R. Eng, Vicki M. Collins, Robert J. Czerniak, Philip M. Gorry, Stewart A. Trzaskos, James M. |
| description | PROSTAGLANDINS have wide-ranging effects in the body and are thought to be important mediators of inflammation. Cyclooxygen-ase (COX) plays a key regulatory role in prostaglandin synthesis, and occurs in both constitutive (COX-1) and inducible (COX-2) isoforms
1,2
. COX-1 is thought to provide cytoprotective effects
3
, whereas COX-2 is both inducible and the major isoform of inflammatory cells
4
. Reduction of prostaglandin production by inhibition of cyclooxygenases appears to be the main mechanism of action of most non-steroidal anti-inflammatory drugs (NSAIDS)
5
. Here we present an animal model of COX-2 deficiency that was generated by gene targeting. Defects in null mice correlating with reduced viability included renal alterations, characteristic of renal dysplasia (100% penetrance), and cardiac fibrosis (50% penetrance). Female Cox-2
−
/
−
mice were infertile. COX-2 deficiency failed to alter inflammatory responses in several standard models, but striking mitigation of endotoxin-induced hepatocellular cytotoxicity was observed. |
| doi_str_mv | 10.1038/378406a0 |
| format | Article |
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1,2
. COX-1 is thought to provide cytoprotective effects
3
, whereas COX-2 is both inducible and the major isoform of inflammatory cells
4
. Reduction of prostaglandin production by inhibition of cyclooxygenases appears to be the main mechanism of action of most non-steroidal anti-inflammatory drugs (NSAIDS)
5
. Here we present an animal model of COX-2 deficiency that was generated by gene targeting. Defects in null mice correlating with reduced viability included renal alterations, characteristic of renal dysplasia (100% penetrance), and cardiac fibrosis (50% penetrance). Female Cox-2
−
/
−
mice were infertile. COX-2 deficiency failed to alter inflammatory responses in several standard models, but striking mitigation of endotoxin-induced hepatocellular cytotoxicity was observed.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/378406a0</identifier><identifier>PMID: 7477380</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Animal models ; Animals ; Anti-inflammatory agents ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Cell Line ; Cyclooxygenase Inhibitors ; Cytotoxicity ; Disease Models, Animal ; Endotoxins ; Female ; Fibrosis ; Gene Targeting ; Genes ; Heart Diseases - enzymology ; Heart Diseases - genetics ; Humanities and Social Sciences ; Infertility, Female - enzymology ; Infertility, Female - genetics ; Inflammation - enzymology ; Inflammation - genetics ; Kidney - abnormalities ; Kidney - embryology ; Kidney - enzymology ; Kidneys ; letter ; Liver - embryology ; Liver - enzymology ; Mice ; Mice, Knockout ; multidisciplinary ; Nonsteroidal anti-inflammatory drugs ; Prostaglandin-Endoperoxide Synthases - drug effects ; Prostaglandin-Endoperoxide Synthases - genetics ; Prostaglandin-Endoperoxide Synthases - physiology ; Rodents ; Science</subject><ispartof>Nature (London), 1995-11, Vol.378 (6555), p.406-409</ispartof><rights>Springer Nature Limited 1995</rights><rights>Copyright Macmillan Journals Ltd. Nov 23, 1995</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c467t-4cdee14766549b194afc0b1aba5dd6cd98eac7773d42428bd3e8348a6a7605743</citedby><cites>FETCH-LOGICAL-c467t-4cdee14766549b194afc0b1aba5dd6cd98eac7773d42428bd3e8348a6a7605743</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/378406a0$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/378406a0$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7477380$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dinchuk, Joseph E.</creatorcontrib><creatorcontrib>Car, Bruce D.</creatorcontrib><creatorcontrib>Focht, Richard J.</creatorcontrib><creatorcontrib>Johnston, Jennifer J.</creatorcontrib><creatorcontrib>Jaffee, Bruce D.</creatorcontrib><creatorcontrib>Covington, Maryanne B.</creatorcontrib><creatorcontrib>Contel, Nancy R.</creatorcontrib><creatorcontrib>Eng, Vicki M.</creatorcontrib><creatorcontrib>Collins, Robert J.</creatorcontrib><creatorcontrib>Czerniak, Philip M.</creatorcontrib><creatorcontrib>Gorry, Stewart A.</creatorcontrib><creatorcontrib>Trzaskos, James M.</creatorcontrib><title>Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>PROSTAGLANDINS have wide-ranging effects in the body and are thought to be important mediators of inflammation. Cyclooxygen-ase (COX) plays a key regulatory role in prostaglandin synthesis, and occurs in both constitutive (COX-1) and inducible (COX-2) isoforms
1,2
. COX-1 is thought to provide cytoprotective effects
3
, whereas COX-2 is both inducible and the major isoform of inflammatory cells
4
. Reduction of prostaglandin production by inhibition of cyclooxygenases appears to be the main mechanism of action of most non-steroidal anti-inflammatory drugs (NSAIDS)
5
. Here we present an animal model of COX-2 deficiency that was generated by gene targeting. Defects in null mice correlating with reduced viability included renal alterations, characteristic of renal dysplasia (100% penetrance), and cardiac fibrosis (50% penetrance). Female Cox-2
−
/
−
mice were infertile. COX-2 deficiency failed to alter inflammatory responses in several standard models, but striking mitigation of endotoxin-induced hepatocellular cytotoxicity was observed.</description><subject>Animal models</subject><subject>Animals</subject><subject>Anti-inflammatory agents</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Cell Line</subject><subject>Cyclooxygenase Inhibitors</subject><subject>Cytotoxicity</subject><subject>Disease Models, Animal</subject><subject>Endotoxins</subject><subject>Female</subject><subject>Fibrosis</subject><subject>Gene Targeting</subject><subject>Genes</subject><subject>Heart Diseases - enzymology</subject><subject>Heart Diseases - genetics</subject><subject>Humanities and Social Sciences</subject><subject>Infertility, Female - enzymology</subject><subject>Infertility, Female - genetics</subject><subject>Inflammation - enzymology</subject><subject>Inflammation - genetics</subject><subject>Kidney - abnormalities</subject><subject>Kidney - embryology</subject><subject>Kidney - enzymology</subject><subject>Kidneys</subject><subject>letter</subject><subject>Liver - embryology</subject><subject>Liver - enzymology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>multidisciplinary</subject><subject>Nonsteroidal anti-inflammatory drugs</subject><subject>Prostaglandin-Endoperoxide Synthases - drug effects</subject><subject>Prostaglandin-Endoperoxide Synthases - genetics</subject><subject>Prostaglandin-Endoperoxide Synthases - physiology</subject><subject>Rodents</subject><subject>Science</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkUFr3DAQhUVoSLZpIX8gYHoozcHpyJIl-ViWtlkIBEJ66cWMpdnFiWxtJC90_30UdptAcshhGJj38WaYx9gphwsOwnwX2khQCAdsxqVWpVRGf2AzgMqUYIQ6Zh9TugOAmmt5xI601FoYmLG_NzSiL7AbQxzQ91NPqcDR5SrQTxTJFf249DgMOIW4LSKldRgT5Wkx9JYKj_a-H1eF3Vofwr_tKhtmebH4xA6X6BN93vcT9ufXz9v5ZXl1_Xsx_3FVWqn0VErriJ6OVrVsOt5IXFroOHZYO6esawyh1flcJytZmc4JMkIaVKgV1FqKE_Z157uO4WFDaWqHPlnyHkcKm9RqrRoQlXgXFKoCblTzLshV00jN6wx-eQXehU3MD01tBVLWjVIqQ992kI0hpUjLdh37AeO25dA-pdf-Ty-jZ3u_TTeQewb3cWX9fKenrIwrii_73ng9AvQDoPU</recordid><startdate>19951123</startdate><enddate>19951123</enddate><creator>Dinchuk, Joseph E.</creator><creator>Car, Bruce D.</creator><creator>Focht, Richard J.</creator><creator>Johnston, Jennifer J.</creator><creator>Jaffee, Bruce D.</creator><creator>Covington, Maryanne B.</creator><creator>Contel, Nancy R.</creator><creator>Eng, Vicki M.</creator><creator>Collins, Robert J.</creator><creator>Czerniak, Philip M.</creator><creator>Gorry, Stewart A.</creator><creator>Trzaskos, James M.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7TG</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PCBAR</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>R05</scope><scope>RC3</scope><scope>S0X</scope><scope>SOI</scope><scope>7SC</scope><scope>7SP</scope><scope>7SR</scope><scope>7TB</scope><scope>7U5</scope><scope>8BQ</scope><scope>F28</scope><scope>JG9</scope><scope>JQ2</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>7X8</scope></search><sort><creationdate>19951123</creationdate><title>Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II</title><author>Dinchuk, Joseph E. ; Car, Bruce D. ; Focht, Richard J. ; Johnston, Jennifer J. ; Jaffee, Bruce D. ; Covington, Maryanne B. ; Contel, Nancy R. ; Eng, Vicki M. ; Collins, Robert J. ; Czerniak, Philip M. ; Gorry, Stewart A. ; Trzaskos, James M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c467t-4cdee14766549b194afc0b1aba5dd6cd98eac7773d42428bd3e8348a6a7605743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Anti-inflammatory agents</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Cell Line</topic><topic>Cyclooxygenase Inhibitors</topic><topic>Cytotoxicity</topic><topic>Disease Models, Animal</topic><topic>Endotoxins</topic><topic>Female</topic><topic>Fibrosis</topic><topic>Gene Targeting</topic><topic>Genes</topic><topic>Heart Diseases - enzymology</topic><topic>Heart Diseases - genetics</topic><topic>Humanities and Social Sciences</topic><topic>Infertility, Female - enzymology</topic><topic>Infertility, Female - genetics</topic><topic>Inflammation - enzymology</topic><topic>Inflammation - genetics</topic><topic>Kidney - abnormalities</topic><topic>Kidney - embryology</topic><topic>Kidney - enzymology</topic><topic>Kidneys</topic><topic>letter</topic><topic>Liver - embryology</topic><topic>Liver - enzymology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>multidisciplinary</topic><topic>Nonsteroidal anti-inflammatory drugs</topic><topic>Prostaglandin-Endoperoxide Synthases - drug effects</topic><topic>Prostaglandin-Endoperoxide Synthases - 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Academic</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dinchuk, Joseph E.</au><au>Car, Bruce D.</au><au>Focht, Richard J.</au><au>Johnston, Jennifer J.</au><au>Jaffee, Bruce D.</au><au>Covington, Maryanne B.</au><au>Contel, Nancy R.</au><au>Eng, Vicki M.</au><au>Collins, Robert J.</au><au>Czerniak, Philip M.</au><au>Gorry, Stewart A.</au><au>Trzaskos, James M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>1995-11-23</date><risdate>1995</risdate><volume>378</volume><issue>6555</issue><spage>406</spage><epage>409</epage><pages>406-409</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>PROSTAGLANDINS have wide-ranging effects in the body and are thought to be important mediators of inflammation. Cyclooxygen-ase (COX) plays a key regulatory role in prostaglandin synthesis, and occurs in both constitutive (COX-1) and inducible (COX-2) isoforms
1,2
. COX-1 is thought to provide cytoprotective effects
3
, whereas COX-2 is both inducible and the major isoform of inflammatory cells
4
. Reduction of prostaglandin production by inhibition of cyclooxygenases appears to be the main mechanism of action of most non-steroidal anti-inflammatory drugs (NSAIDS)
5
. Here we present an animal model of COX-2 deficiency that was generated by gene targeting. Defects in null mice correlating with reduced viability included renal alterations, characteristic of renal dysplasia (100% penetrance), and cardiac fibrosis (50% penetrance). Female Cox-2
−
/
−
mice were infertile. COX-2 deficiency failed to alter inflammatory responses in several standard models, but striking mitigation of endotoxin-induced hepatocellular cytotoxicity was observed.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>7477380</pmid><doi>10.1038/378406a0</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 1995-11, Vol.378 (6555), p.406-409 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_77690323 |
| source | MEDLINE; Nature Journals Online; SpringerLink Journals - AutoHoldings |
| subjects | Animal models Animals Anti-inflammatory agents Anti-Inflammatory Agents, Non-Steroidal - pharmacology Cell Line Cyclooxygenase Inhibitors Cytotoxicity Disease Models, Animal Endotoxins Female Fibrosis Gene Targeting Genes Heart Diseases - enzymology Heart Diseases - genetics Humanities and Social Sciences Infertility, Female - enzymology Infertility, Female - genetics Inflammation - enzymology Inflammation - genetics Kidney - abnormalities Kidney - embryology Kidney - enzymology Kidneys letter Liver - embryology Liver - enzymology Mice Mice, Knockout multidisciplinary Nonsteroidal anti-inflammatory drugs Prostaglandin-Endoperoxide Synthases - drug effects Prostaglandin-Endoperoxide Synthases - genetics Prostaglandin-Endoperoxide Synthases - physiology Rodents Science |
| title | Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II |
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