JNK mediates hepatic ischemia reperfusion injury
Hepatic ischemia followed by reperfusion (I/R) is a major clinical problem during transplantation, liver resection for tumor, and circulatory shock, producing apoptosis and necrosis. Although several intracellular signal molecules are induced following I/R including NF-κB and c-Jun N terminal kinase...
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| Veröffentlicht in: | Journal of hepatology 2005-06, Vol.42 (6), p.850-859 |
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| creator | Uehara, Tetsuya Bennett, Brydon Sakata, Steve T. Satoh, Yoshitaka Bilter, Graham K. Westwick, John K. Brenner, David A. |
| description | Hepatic ischemia followed by reperfusion (I/R) is a major clinical problem during transplantation, liver resection for tumor, and circulatory shock, producing apoptosis and necrosis. Although several intracellular signal molecules are induced following I/R including NF-κB and c-Jun N terminal kinase (JNK), their roles in I/R injury are largely unknown. The aim of this study is to assess the role of JNK during warm I/R injury using novel selective JNK inhibitors.
Male Wistar rats (200±25
g) are pretreated with vehicle or with one of three compounds (CC0209766, CC0223105, and CC-401), which are reversible, highly selective, ATP-competitive inhibitors of JNK. In the first study, rats are assessed for survival using a model of ischemia to 70% of the liver for 90
min followed by 30% hepatectomy of the non-ischemic lobes and then reperfusion. In the second study, rats are assessed for liver injury resulting from 60 or 90
min of ischemia followed by reperfusion with analysis over time of hepatic histology, serum ALT, hepatic caspase-3 activation, cytochrome
c release, and lipid peroxidation.
In the I/R survival model, vehicle-treated rats have a 7-day survival of 20–40%, while rats treated with the three different JNK inhibitors have survival rates of 60–100% (
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| doi_str_mv | 10.1016/j.jhep.2005.01.030 |
| format | Article |
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Male Wistar rats (200±25
g) are pretreated with vehicle or with one of three compounds (CC0209766, CC0223105, and CC-401), which are reversible, highly selective, ATP-competitive inhibitors of JNK. In the first study, rats are assessed for survival using a model of ischemia to 70% of the liver for 90
min followed by 30% hepatectomy of the non-ischemic lobes and then reperfusion. In the second study, rats are assessed for liver injury resulting from 60 or 90
min of ischemia followed by reperfusion with analysis over time of hepatic histology, serum ALT, hepatic caspase-3 activation, cytochrome
c release, and lipid peroxidation.
In the I/R survival model, vehicle-treated rats have a 7-day survival of 20–40%, while rats treated with the three different JNK inhibitors have survival rates of 60–100% (
P<0.05). The decrease in mortality correlates with improved hepatic histology and serum ALT levels. Vehicle treated rats have pericentral necrosis, neutrophil infiltration, and some apoptosis in both hepatocytes and sinusoidal endothelial cells, while JNK inhibitors significantly decrease both types of cell death. JNK inhibitors decrease caspase-3 activation, cytochrome
c release from mitochondria, and lipid peroxidation. JNK inhibition transiently blocks phosphorylation of c-Jun at an early time point after reperfusion, and AP-1 activation is also substantially blocked. JNK inhibition blocks the upregulation of the pro-apoptotic Bak protein and the degradation of Bid.
Thus, JNK inhibitors decrease both necrosis and apoptosis, suggesting that JNK activity induces cell death by both pathways.</description><identifier>ISSN: 0168-8278</identifier><identifier>EISSN: 1600-0641</identifier><identifier>DOI: 10.1016/j.jhep.2005.01.030</identifier><identifier>PMID: 15885356</identifier><identifier>CODEN: JOHEEC</identifier><language>eng</language><publisher>Oxford: Elsevier B.V</publisher><subject>Animals ; Apoptosis ; Biological and medical sciences ; c-Jun ; Caspase 3 ; Caspases - metabolism ; Cytochromes c - metabolism ; Cytoplasm - metabolism ; Disease Models, Animal ; Enzyme Inhibitors - pharmacology ; Gastroenterology. Liver. Pancreas. Abdomen ; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors ; JNK Mitogen-Activated Protein Kinases - metabolism ; Lipid Peroxidation - drug effects ; Liver ; Liver - enzymology ; Liver - pathology ; Liver, biliary tract, pancreas, portal circulation, spleen ; Male ; Medical sciences ; Mitochondria - metabolism ; Necrosis ; Rats ; Rats, Wistar ; Reperfusion Injury - drug therapy ; Reperfusion Injury - metabolism ; Reperfusion Injury - mortality ; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases ; Surgery of the digestive system ; Tumor necrosis factor α ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>Journal of hepatology, 2005-06, Vol.42 (6), p.850-859</ispartof><rights>2005 European Association for the Study of the Liver</rights><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c384t-cc640b59caa50c7a02c865d042851987e5e99273266b300b81b39d8bac4470633</citedby><cites>FETCH-LOGICAL-c384t-cc640b59caa50c7a02c865d042851987e5e99273266b300b81b39d8bac4470633</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jhep.2005.01.030$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16807824$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15885356$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Uehara, Tetsuya</creatorcontrib><creatorcontrib>Bennett, Brydon</creatorcontrib><creatorcontrib>Sakata, Steve T.</creatorcontrib><creatorcontrib>Satoh, Yoshitaka</creatorcontrib><creatorcontrib>Bilter, Graham K.</creatorcontrib><creatorcontrib>Westwick, John K.</creatorcontrib><creatorcontrib>Brenner, David A.</creatorcontrib><title>JNK mediates hepatic ischemia reperfusion injury</title><title>Journal of hepatology</title><addtitle>J Hepatol</addtitle><description>Hepatic ischemia followed by reperfusion (I/R) is a major clinical problem during transplantation, liver resection for tumor, and circulatory shock, producing apoptosis and necrosis. Although several intracellular signal molecules are induced following I/R including NF-κB and c-Jun N terminal kinase (JNK), their roles in I/R injury are largely unknown. The aim of this study is to assess the role of JNK during warm I/R injury using novel selective JNK inhibitors.
Male Wistar rats (200±25
g) are pretreated with vehicle or with one of three compounds (CC0209766, CC0223105, and CC-401), which are reversible, highly selective, ATP-competitive inhibitors of JNK. In the first study, rats are assessed for survival using a model of ischemia to 70% of the liver for 90
min followed by 30% hepatectomy of the non-ischemic lobes and then reperfusion. In the second study, rats are assessed for liver injury resulting from 60 or 90
min of ischemia followed by reperfusion with analysis over time of hepatic histology, serum ALT, hepatic caspase-3 activation, cytochrome
c release, and lipid peroxidation.
In the I/R survival model, vehicle-treated rats have a 7-day survival of 20–40%, while rats treated with the three different JNK inhibitors have survival rates of 60–100% (
P<0.05). The decrease in mortality correlates with improved hepatic histology and serum ALT levels. Vehicle treated rats have pericentral necrosis, neutrophil infiltration, and some apoptosis in both hepatocytes and sinusoidal endothelial cells, while JNK inhibitors significantly decrease both types of cell death. JNK inhibitors decrease caspase-3 activation, cytochrome
c release from mitochondria, and lipid peroxidation. JNK inhibition transiently blocks phosphorylation of c-Jun at an early time point after reperfusion, and AP-1 activation is also substantially blocked. JNK inhibition blocks the upregulation of the pro-apoptotic Bak protein and the degradation of Bid.
Thus, JNK inhibitors decrease both necrosis and apoptosis, suggesting that JNK activity induces cell death by both pathways.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>c-Jun</subject><subject>Caspase 3</subject><subject>Caspases - metabolism</subject><subject>Cytochromes c - metabolism</subject><subject>Cytoplasm - metabolism</subject><subject>Disease Models, Animal</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors</subject><subject>JNK Mitogen-Activated Protein Kinases - metabolism</subject><subject>Lipid Peroxidation - drug effects</subject><subject>Liver</subject><subject>Liver - enzymology</subject><subject>Liver - pathology</subject><subject>Liver, biliary tract, pancreas, portal circulation, spleen</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mitochondria - metabolism</subject><subject>Necrosis</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Reperfusion Injury - drug therapy</subject><subject>Reperfusion Injury - metabolism</subject><subject>Reperfusion Injury - mortality</subject><subject>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</subject><subject>Surgery of the digestive system</subject><subject>Tumor necrosis factor α</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>0168-8278</issn><issn>1600-0641</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kDtPwzAUhS0EoqXwBxhQFtgSrpPYcSQWVPGuYIHZcpwb1VFe2AlS_z2uGomN6S7fPTrnI-SSQkSB8ts6qrc4RDEAi4BGkMARWVIOEAJP6TFZekiEIs7Egpw5VwN4JE9PyYIyIVjC-JLA6_tb0GJp1Igu8HFqNDowTm-xNSqwOKCtJmf6LjBdPdndOTmpVOPwYr4r8vX48Ll-DjcfTy_r-02oE5GOodY8hYLlWikGOlMQa8FZCWksGM1FhgzzPM6SmPMiASgELZK8FIXSaZoBT5IVuTnkDrb_ntCNsvWtsGlUh_3kJM8E9cuYB-MDqG3vnMVKDta0yu4kBbn3JGu59yT3niRQ6SX4p6s5fSr8-r-XWYwHrmdAOa2ayqpOG_fHcQGZiFPP3R049C5-DFrptMFOe6MW9SjL3vzX4xfhIIQi</recordid><startdate>20050601</startdate><enddate>20050601</enddate><creator>Uehara, Tetsuya</creator><creator>Bennett, Brydon</creator><creator>Sakata, Steve T.</creator><creator>Satoh, Yoshitaka</creator><creator>Bilter, Graham K.</creator><creator>Westwick, John K.</creator><creator>Brenner, David A.</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><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>20050601</creationdate><title>JNK mediates hepatic ischemia reperfusion injury</title><author>Uehara, Tetsuya ; Bennett, Brydon ; Sakata, Steve T. ; Satoh, Yoshitaka ; Bilter, Graham K. ; Westwick, John K. ; Brenner, David A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c384t-cc640b59caa50c7a02c865d042851987e5e99273266b300b81b39d8bac4470633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>c-Jun</topic><topic>Caspase 3</topic><topic>Caspases - metabolism</topic><topic>Cytochromes c - metabolism</topic><topic>Cytoplasm - metabolism</topic><topic>Disease Models, Animal</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors</topic><topic>JNK Mitogen-Activated Protein Kinases - metabolism</topic><topic>Lipid Peroxidation - drug effects</topic><topic>Liver</topic><topic>Liver - enzymology</topic><topic>Liver - pathology</topic><topic>Liver, biliary tract, pancreas, portal circulation, spleen</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mitochondria - metabolism</topic><topic>Necrosis</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Reperfusion Injury - drug therapy</topic><topic>Reperfusion Injury - metabolism</topic><topic>Reperfusion Injury - mortality</topic><topic>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</topic><topic>Surgery of the digestive system</topic><topic>Tumor necrosis factor α</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Uehara, Tetsuya</creatorcontrib><creatorcontrib>Bennett, Brydon</creatorcontrib><creatorcontrib>Sakata, Steve T.</creatorcontrib><creatorcontrib>Satoh, Yoshitaka</creatorcontrib><creatorcontrib>Bilter, Graham K.</creatorcontrib><creatorcontrib>Westwick, John K.</creatorcontrib><creatorcontrib>Brenner, David A.</creatorcontrib><collection>Pascal-Francis</collection><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>Journal of hepatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Uehara, Tetsuya</au><au>Bennett, Brydon</au><au>Sakata, Steve T.</au><au>Satoh, Yoshitaka</au><au>Bilter, Graham K.</au><au>Westwick, John K.</au><au>Brenner, David A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>JNK mediates hepatic ischemia reperfusion injury</atitle><jtitle>Journal of hepatology</jtitle><addtitle>J Hepatol</addtitle><date>2005-06-01</date><risdate>2005</risdate><volume>42</volume><issue>6</issue><spage>850</spage><epage>859</epage><pages>850-859</pages><issn>0168-8278</issn><eissn>1600-0641</eissn><coden>JOHEEC</coden><abstract>Hepatic ischemia followed by reperfusion (I/R) is a major clinical problem during transplantation, liver resection for tumor, and circulatory shock, producing apoptosis and necrosis. Although several intracellular signal molecules are induced following I/R including NF-κB and c-Jun N terminal kinase (JNK), their roles in I/R injury are largely unknown. The aim of this study is to assess the role of JNK during warm I/R injury using novel selective JNK inhibitors.
Male Wistar rats (200±25
g) are pretreated with vehicle or with one of three compounds (CC0209766, CC0223105, and CC-401), which are reversible, highly selective, ATP-competitive inhibitors of JNK. In the first study, rats are assessed for survival using a model of ischemia to 70% of the liver for 90
min followed by 30% hepatectomy of the non-ischemic lobes and then reperfusion. In the second study, rats are assessed for liver injury resulting from 60 or 90
min of ischemia followed by reperfusion with analysis over time of hepatic histology, serum ALT, hepatic caspase-3 activation, cytochrome
c release, and lipid peroxidation.
In the I/R survival model, vehicle-treated rats have a 7-day survival of 20–40%, while rats treated with the three different JNK inhibitors have survival rates of 60–100% (
P<0.05). The decrease in mortality correlates with improved hepatic histology and serum ALT levels. Vehicle treated rats have pericentral necrosis, neutrophil infiltration, and some apoptosis in both hepatocytes and sinusoidal endothelial cells, while JNK inhibitors significantly decrease both types of cell death. JNK inhibitors decrease caspase-3 activation, cytochrome
c release from mitochondria, and lipid peroxidation. JNK inhibition transiently blocks phosphorylation of c-Jun at an early time point after reperfusion, and AP-1 activation is also substantially blocked. JNK inhibition blocks the upregulation of the pro-apoptotic Bak protein and the degradation of Bid.
Thus, JNK inhibitors decrease both necrosis and apoptosis, suggesting that JNK activity induces cell death by both pathways.</abstract><cop>Oxford</cop><pub>Elsevier B.V</pub><pmid>15885356</pmid><doi>10.1016/j.jhep.2005.01.030</doi><tpages>10</tpages></addata></record> |
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| subjects | Animals Apoptosis Biological and medical sciences c-Jun Caspase 3 Caspases - metabolism Cytochromes c - metabolism Cytoplasm - metabolism Disease Models, Animal Enzyme Inhibitors - pharmacology Gastroenterology. Liver. Pancreas. Abdomen JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors JNK Mitogen-Activated Protein Kinases - metabolism Lipid Peroxidation - drug effects Liver Liver - enzymology Liver - pathology Liver, biliary tract, pancreas, portal circulation, spleen Male Medical sciences Mitochondria - metabolism Necrosis Rats Rats, Wistar Reperfusion Injury - drug therapy Reperfusion Injury - metabolism Reperfusion Injury - mortality Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases Surgery of the digestive system Tumor necrosis factor α Tumor Necrosis Factor-alpha - metabolism |
| title | JNK mediates hepatic ischemia reperfusion injury |
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