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Rho‐kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats
Author(s) -
Kuroda Shintaro,
Tashiro Hirotaka,
Kimura Yasuhiro,
Hirata Kaori,
Tsutada Misaki,
Mikuriya Yoshihiro,
Kobayashi Tsuyoshi,
Amano Hironobu,
Tanaka Yuka,
Ohdan Hideki
Publication year - 2015
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1002/lt.24020
Subject(s) - medicine , steatosis , reperfusion injury , pharmacology , ischemia , liver transplantation , rho kinase inhibitor , hepatic stellate cell , liver injury , rho associated protein kinase , transplantation , kinase , chemistry , biochemistry
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.