Rho‐kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats
Rho‐kinase (ROCK) inhibitors improve liver blood flow after ischemia/reperfusion (IR) injury, especially in the setting of steatosis, by decreasing the resistance of intrahepatic microcirculation through hepatic stellate cell (HSC) relaxation. However, the systemic administration of ROCK inhibitors...
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| Veröffentlicht in: | Liver transplantation 2015-01, Vol.21 (1), p.123-131 |
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| creator | Kuroda, Shintaro Tashiro, Hirotaka Kimura, Yasuhiro Hirata, Kaori Tsutada, Misaki Mikuriya, Yoshihiro Kobayashi, Tsuyoshi Amano, Hironobu Tanaka, Yuka Ohdan, Hideki |
| description | Rho‐kinase (ROCK) inhibitors improve liver blood flow after ischemia/reperfusion (IR) injury, especially in the setting of steatosis, by decreasing the resistance of intrahepatic microcirculation through hepatic stellate cell (HSC) relaxation. However, the systemic administration of ROCK inhibitors causes severe hypotension; therefore, liver‐specific ROCK inhibition is required. Here, we tested vitamin A (VA)–coupled liposomes carrying the ROCK inhibitor Y‐27632 for targeted HSCs in steatotic rats. Rat livers with steatosis induced by a choline‐deficient diet were subjected to IR injury. The delivery site and effect of the ROCK inhibitor were investigated. After liposomal Y‐27632 injection, the survival rate after IR, the liver blood flow, the portal perfused pressure, and the hemodynamics were investigated. Immunohistochemical studies showed VA–coupled liposome accumulation in livers. Liposomal Y‐27632 was 100‐fold more effective in inhibiting HSC activation than free Y‐27632. Liposomal Y‐27632 improved the survival rate after IR injury, the liver blood flow, and the portal perfusion pressure without severe hypotension. In contrast, untargeted Y‐27632 elicited severe systemic hypotension. We conclude that VA–coupled liposomes carrying the ROCK inhibitor yield enhanced drug accumulation in the liver and thus mitigate IR injury in the steatotic liver and reduce major systemic adversity. Liver Transpl 21:123‐131, 2015. © 2014 AASLD. |
| doi_str_mv | 10.1002/lt.24020 |
| format | Article |
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However, the systemic administration of ROCK inhibitors causes severe hypotension; therefore, liver‐specific ROCK inhibition is required. Here, we tested vitamin A (VA)–coupled liposomes carrying the ROCK inhibitor Y‐27632 for targeted HSCs in steatotic rats. Rat livers with steatosis induced by a choline‐deficient diet were subjected to IR injury. The delivery site and effect of the ROCK inhibitor were investigated. After liposomal Y‐27632 injection, the survival rate after IR, the liver blood flow, the portal perfused pressure, and the hemodynamics were investigated. Immunohistochemical studies showed VA–coupled liposome accumulation in livers. Liposomal Y‐27632 was 100‐fold more effective in inhibiting HSC activation than free Y‐27632. Liposomal Y‐27632 improved the survival rate after IR injury, the liver blood flow, and the portal perfusion pressure without severe hypotension. In contrast, untargeted Y‐27632 elicited severe systemic hypotension. We conclude that VA–coupled liposomes carrying the ROCK inhibitor yield enhanced drug accumulation in the liver and thus mitigate IR injury in the steatotic liver and reduce major systemic adversity. Liver Transpl 21:123‐131, 2015. © 2014 AASLD.</description><identifier>ISSN: 1527-6465</identifier><identifier>EISSN: 1527-6473</identifier><identifier>DOI: 10.1002/lt.24020</identifier><identifier>PMID: 25307969</identifier><identifier>CODEN: LITRFO</identifier><language>eng</language><publisher>United States: Wolters Kluwer Health, Inc</publisher><subject>Amides - administration & dosage ; Amides - pharmacology ; Amides - toxicity ; Animals ; Arterial Pressure - drug effects ; Cells, Cultured ; Chemistry, Pharmaceutical ; Choline Deficiency - complications ; Cytoprotection ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Fatty Liver - drug therapy ; Fatty Liver - enzymology ; Fatty Liver - etiology ; Fatty Liver - pathology ; Fatty Liver - physiopathology ; Hepatic Stellate Cells - drug effects ; Hepatic Stellate Cells - enzymology ; Hepatic Stellate Cells - pathology ; Hypotension - chemically induced ; Hypotension - enzymology ; Hypotension - physiopathology ; Liposomes ; Liver - blood supply ; Liver - drug effects ; Liver - enzymology ; Liver - pathology ; Liver Circulation - drug effects ; Male ; Portal Pressure - drug effects ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - toxicity ; Pyridines - administration & dosage ; Pyridines - pharmacology ; Pyridines - toxicity ; Rats, Wistar ; Reperfusion Injury - enzymology ; Reperfusion Injury - etiology ; Reperfusion Injury - pathology ; Reperfusion Injury - physiopathology ; Reperfusion Injury - prevention & control ; rho-Associated Kinases - antagonists & inhibitors ; rho-Associated Kinases - metabolism ; Time Factors</subject><ispartof>Liver transplantation, 2015-01, Vol.21 (1), p.123-131</ispartof><rights>2014 American Association for the Study of Liver Diseases</rights><rights>2014 American Association for the Study of Liver Diseases.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3450-71d25916ed9cb5be4e1a1b378f0d37cccc61c4dc0d83eadad7d220325f82710c3</citedby><cites>FETCH-LOGICAL-c3450-71d25916ed9cb5be4e1a1b378f0d37cccc61c4dc0d83eadad7d220325f82710c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Flt.24020$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Flt.24020$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25307969$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kuroda, Shintaro</creatorcontrib><creatorcontrib>Tashiro, Hirotaka</creatorcontrib><creatorcontrib>Kimura, Yasuhiro</creatorcontrib><creatorcontrib>Hirata, Kaori</creatorcontrib><creatorcontrib>Tsutada, Misaki</creatorcontrib><creatorcontrib>Mikuriya, Yoshihiro</creatorcontrib><creatorcontrib>Kobayashi, Tsuyoshi</creatorcontrib><creatorcontrib>Amano, Hironobu</creatorcontrib><creatorcontrib>Tanaka, Yuka</creatorcontrib><creatorcontrib>Ohdan, Hideki</creatorcontrib><title>Rho‐kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats</title><title>Liver transplantation</title><addtitle>Liver Transpl</addtitle><description>Rho‐kinase (ROCK) inhibitors improve liver blood flow after ischemia/reperfusion (IR) injury, especially in the setting of steatosis, by decreasing the resistance of intrahepatic microcirculation through hepatic stellate cell (HSC) relaxation. However, the systemic administration of ROCK inhibitors causes severe hypotension; therefore, liver‐specific ROCK inhibition is required. Here, we tested vitamin A (VA)–coupled liposomes carrying the ROCK inhibitor Y‐27632 for targeted HSCs in steatotic rats. Rat livers with steatosis induced by a choline‐deficient diet were subjected to IR injury. The delivery site and effect of the ROCK inhibitor were investigated. After liposomal Y‐27632 injection, the survival rate after IR, the liver blood flow, the portal perfused pressure, and the hemodynamics were investigated. Immunohistochemical studies showed VA–coupled liposome accumulation in livers. Liposomal Y‐27632 was 100‐fold more effective in inhibiting HSC activation than free Y‐27632. Liposomal Y‐27632 improved the survival rate after IR injury, the liver blood flow, and the portal perfusion pressure without severe hypotension. In contrast, untargeted Y‐27632 elicited severe systemic hypotension. We conclude that VA–coupled liposomes carrying the ROCK inhibitor yield enhanced drug accumulation in the liver and thus mitigate IR injury in the steatotic liver and reduce major systemic adversity. Liver Transpl 21:123‐131, 2015. © 2014 AASLD.</description><subject>Amides - administration & dosage</subject><subject>Amides - pharmacology</subject><subject>Amides - toxicity</subject><subject>Animals</subject><subject>Arterial Pressure - drug effects</subject><subject>Cells, Cultured</subject><subject>Chemistry, Pharmaceutical</subject><subject>Choline Deficiency - complications</subject><subject>Cytoprotection</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Fatty Liver - drug therapy</subject><subject>Fatty Liver - enzymology</subject><subject>Fatty Liver - etiology</subject><subject>Fatty Liver - pathology</subject><subject>Fatty Liver - physiopathology</subject><subject>Hepatic Stellate Cells - drug effects</subject><subject>Hepatic Stellate Cells - enzymology</subject><subject>Hepatic Stellate Cells - pathology</subject><subject>Hypotension - chemically induced</subject><subject>Hypotension - enzymology</subject><subject>Hypotension - physiopathology</subject><subject>Liposomes</subject><subject>Liver - blood supply</subject><subject>Liver - drug effects</subject><subject>Liver - enzymology</subject><subject>Liver - pathology</subject><subject>Liver Circulation - drug effects</subject><subject>Male</subject><subject>Portal Pressure - drug effects</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - toxicity</subject><subject>Pyridines - administration & dosage</subject><subject>Pyridines - pharmacology</subject><subject>Pyridines - toxicity</subject><subject>Rats, Wistar</subject><subject>Reperfusion Injury - enzymology</subject><subject>Reperfusion Injury - etiology</subject><subject>Reperfusion Injury - pathology</subject><subject>Reperfusion Injury - physiopathology</subject><subject>Reperfusion Injury - prevention & control</subject><subject>rho-Associated Kinases - antagonists & inhibitors</subject><subject>rho-Associated Kinases - metabolism</subject><subject>Time Factors</subject><issn>1527-6465</issn><issn>1527-6473</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kctKxDAUhoMoXkbBJ5CCGzfVXHrLUsQbDAii65Imp9OMbTMm6cjsfAN9Rp_EODMqCGZzAv_3fyQchA4JPiUY07PWn9IEU7yBdklK8zhLcrb5c8_SHbTn3BRjQlKOt9EOTRnOecZ30dt9Yz5e3590LxxEum90pb2xkRd2Al73k8g3ELV6DjaaWZhD712knWyg0-LMwgxsPTht-tCdDnYRxrLhPAhvvJbr7ov2jRl81IlpsLtFyLsQChVCp_2yZ4V3-2irFq2Dg_Ucocery4eLm3h8d317cT6OJUtSHOdE0ZSTDBSXVVpBAkSQiuVFjRXLZTgZkYmSWBUMhBIqV5RiRtO6oDnBko3Qyco7s-Z5AOfLLvwK2lb0YAZXkiwJeFFwHtDjP-jUDLYPrwsUKzjmPGG_QmmNcxbqcmZ1J-yiJLj8WlLZ-nK5pIAerYVD1YH6Ab-3EoB4BbzoFhb_isrxw0r4Cd9EnwQ</recordid><startdate>201501</startdate><enddate>201501</enddate><creator>Kuroda, Shintaro</creator><creator>Tashiro, Hirotaka</creator><creator>Kimura, Yasuhiro</creator><creator>Hirata, Kaori</creator><creator>Tsutada, Misaki</creator><creator>Mikuriya, Yoshihiro</creator><creator>Kobayashi, Tsuyoshi</creator><creator>Amano, Hironobu</creator><creator>Tanaka, Yuka</creator><creator>Ohdan, Hideki</creator><general>Wolters Kluwer Health, Inc</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>K9.</scope><scope>7X8</scope></search><sort><creationdate>201501</creationdate><title>Rho‐kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats</title><author>Kuroda, Shintaro ; Tashiro, Hirotaka ; Kimura, Yasuhiro ; Hirata, Kaori ; Tsutada, Misaki ; Mikuriya, Yoshihiro ; Kobayashi, Tsuyoshi ; Amano, Hironobu ; Tanaka, Yuka ; Ohdan, Hideki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3450-71d25916ed9cb5be4e1a1b378f0d37cccc61c4dc0d83eadad7d220325f82710c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Amides - administration & dosage</topic><topic>Amides - pharmacology</topic><topic>Amides - toxicity</topic><topic>Animals</topic><topic>Arterial Pressure - drug effects</topic><topic>Cells, Cultured</topic><topic>Chemistry, Pharmaceutical</topic><topic>Choline Deficiency - complications</topic><topic>Cytoprotection</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Fatty Liver - drug therapy</topic><topic>Fatty Liver - enzymology</topic><topic>Fatty Liver - etiology</topic><topic>Fatty Liver - pathology</topic><topic>Fatty Liver - physiopathology</topic><topic>Hepatic Stellate Cells - drug effects</topic><topic>Hepatic Stellate Cells - enzymology</topic><topic>Hepatic Stellate Cells - pathology</topic><topic>Hypotension - chemically induced</topic><topic>Hypotension - enzymology</topic><topic>Hypotension - physiopathology</topic><topic>Liposomes</topic><topic>Liver - blood supply</topic><topic>Liver - drug effects</topic><topic>Liver - enzymology</topic><topic>Liver - pathology</topic><topic>Liver Circulation - drug effects</topic><topic>Male</topic><topic>Portal Pressure - drug effects</topic><topic>Protein Kinase Inhibitors - administration & dosage</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - toxicity</topic><topic>Pyridines - administration & dosage</topic><topic>Pyridines - pharmacology</topic><topic>Pyridines - toxicity</topic><topic>Rats, Wistar</topic><topic>Reperfusion Injury - enzymology</topic><topic>Reperfusion Injury - etiology</topic><topic>Reperfusion Injury - pathology</topic><topic>Reperfusion Injury - physiopathology</topic><topic>Reperfusion Injury - prevention & control</topic><topic>rho-Associated Kinases - antagonists & inhibitors</topic><topic>rho-Associated Kinases - metabolism</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kuroda, Shintaro</creatorcontrib><creatorcontrib>Tashiro, Hirotaka</creatorcontrib><creatorcontrib>Kimura, Yasuhiro</creatorcontrib><creatorcontrib>Hirata, Kaori</creatorcontrib><creatorcontrib>Tsutada, Misaki</creatorcontrib><creatorcontrib>Mikuriya, Yoshihiro</creatorcontrib><creatorcontrib>Kobayashi, Tsuyoshi</creatorcontrib><creatorcontrib>Amano, Hironobu</creatorcontrib><creatorcontrib>Tanaka, Yuka</creatorcontrib><creatorcontrib>Ohdan, Hideki</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Liver transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kuroda, Shintaro</au><au>Tashiro, Hirotaka</au><au>Kimura, Yasuhiro</au><au>Hirata, Kaori</au><au>Tsutada, Misaki</au><au>Mikuriya, Yoshihiro</au><au>Kobayashi, Tsuyoshi</au><au>Amano, Hironobu</au><au>Tanaka, Yuka</au><au>Ohdan, Hideki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rho‐kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats</atitle><jtitle>Liver transplantation</jtitle><addtitle>Liver Transpl</addtitle><date>2015-01</date><risdate>2015</risdate><volume>21</volume><issue>1</issue><spage>123</spage><epage>131</epage><pages>123-131</pages><issn>1527-6465</issn><eissn>1527-6473</eissn><coden>LITRFO</coden><abstract>Rho‐kinase (ROCK) inhibitors improve liver blood flow after ischemia/reperfusion (IR) injury, especially in the setting of steatosis, by decreasing the resistance of intrahepatic microcirculation through hepatic stellate cell (HSC) relaxation. However, the systemic administration of ROCK inhibitors causes severe hypotension; therefore, liver‐specific ROCK inhibition is required. Here, we tested vitamin A (VA)–coupled liposomes carrying the ROCK inhibitor Y‐27632 for targeted HSCs in steatotic rats. Rat livers with steatosis induced by a choline‐deficient diet were subjected to IR injury. The delivery site and effect of the ROCK inhibitor were investigated. After liposomal Y‐27632 injection, the survival rate after IR, the liver blood flow, the portal perfused pressure, and the hemodynamics were investigated. Immunohistochemical studies showed VA–coupled liposome accumulation in livers. Liposomal Y‐27632 was 100‐fold more effective in inhibiting HSC activation than free Y‐27632. Liposomal Y‐27632 improved the survival rate after IR injury, the liver blood flow, and the portal perfusion pressure without severe hypotension. In contrast, untargeted Y‐27632 elicited severe systemic hypotension. We conclude that VA–coupled liposomes carrying the ROCK inhibitor yield enhanced drug accumulation in the liver and thus mitigate IR injury in the steatotic liver and reduce major systemic adversity. Liver Transpl 21:123‐131, 2015. © 2014 AASLD.</abstract><cop>United States</cop><pub>Wolters Kluwer Health, Inc</pub><pmid>25307969</pmid><doi>10.1002/lt.24020</doi><tpages>9</tpages></addata></record> |
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| subjects | Amides - administration & dosage Amides - pharmacology Amides - toxicity Animals Arterial Pressure - drug effects Cells, Cultured Chemistry, Pharmaceutical Choline Deficiency - complications Cytoprotection Disease Models, Animal Dose-Response Relationship, Drug Fatty Liver - drug therapy Fatty Liver - enzymology Fatty Liver - etiology Fatty Liver - pathology Fatty Liver - physiopathology Hepatic Stellate Cells - drug effects Hepatic Stellate Cells - enzymology Hepatic Stellate Cells - pathology Hypotension - chemically induced Hypotension - enzymology Hypotension - physiopathology Liposomes Liver - blood supply Liver - drug effects Liver - enzymology Liver - pathology Liver Circulation - drug effects Male Portal Pressure - drug effects Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - toxicity Pyridines - administration & dosage Pyridines - pharmacology Pyridines - toxicity Rats, Wistar Reperfusion Injury - enzymology Reperfusion Injury - etiology Reperfusion Injury - pathology Reperfusion Injury - physiopathology Reperfusion Injury - prevention & control rho-Associated Kinases - antagonists & inhibitors rho-Associated Kinases - metabolism Time Factors |
| title | Rho‐kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats |
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