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 VAcoupled 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.

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

“…Resolvin D1, which is an endogenous pro-resolving lipid mediator, was reported to polarizing macrophage to M2 phenotype and inhibit liver IRI [20]. ROCK inhibitors were showed a protective effect in liver IRI in the previous study [44,45]. But they thought that effect is hepatic stellate cell dependent.…”

Vitamin A‐coupled liposomal Rho‐kinase inhibitor ameliorates liver fibrosis without systemic adverse effects

“…We also evaluated the effects of systemic administration of Y‐27632 (10 mg/kg) on ischemia–reperfusion injury in rats and found that this compound improved postoperative liver function and survival rate, but induced a dramatic decrease in blood pressure, supporting that high systemic doses of ROCK inhibitors were necessary for improvement of liver fibrosis and could result in systemic adverse effects, such as hypotension. Therefore, we developed a new DDS, VA‐Lip‐Y, and showed that VA‐Lip‐Y mitigated ischemia–reperfusion injury in the steatotic liver and reduced major systemic adverse effects, such as hypotension . Similarly, in this study, VA‐Lip‐Y treatment suppressed liver fibrosis at a dose of 0.2 mg/kg ROCK inhibitor.…”

“…A VA‐coupled liposomal ROCK inhibitor was prepared as previously described . Briefly, empty liposomes (Coatsome EL‐N‐01; NOF, Tokyo, Japan) were prepared to deliver ROCK inhibitor (Y‐27632 [Y]; Wako, Osaka, Japan), and 25 mg empty liposomes were added to 400 μL Y solution (15 mg/mL in phosphate‐buffered saline [PBS]; liposomes carrying Y‐27632 [Lip‐Y]).…”

Primary non‐function is frequently associated with fatty liver allografts and high mortality after re‐transplantation

“…New biomarkers including miRNAs may help in predicting risk for PNF. Lastly, recent preclinical research suggests Rho‐kinase inhibitor treatment to prevent extensive ischaemia‐reperfusion injury in steatotic allografts without major systemic adversity thus broadening the horizon of pharmacological interventions in the use of fatty liver allografts …”