title: Rho-kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats.
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.
authors.affiliation: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kuroda
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tashiro
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kimura
authors.forename: Kaori
authors.initials: K
authors.lastname: Hirata
authors.forename: Misaki
authors.initials: M
authors.lastname: Tsutada
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Mikuriya
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Hironobu
authors.initials: H
authors.lastname: Amano
authors.forename: Yuka
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
mesh_terms: D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D002796:Choline Deficiency / Q000150:complications; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007022:Hypotension / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D008081:Liposomes; D008099:Liver / Q000098:blood supply* / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D017082:Portal Pressure / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D008081:Liposomes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; D054460:rho-Associated Kinases