ROCK inhibitor Y-27632 prevents primary graft non-function caused by warm ischemia/reperfusion in rat liver transplantation

Abstract.

Hepatic stellate cells (HSCs) can easily be activated by ischemia/reperfusion, and this activation results in hepatic microcirculatory disturbance by cell contraction. ROCK is one of the key regulators of the motility of HSCs, and Y-27632 suppresses the activation of HSCs. We examined whether Y-27632 treatment prevents primary graft non-function caused by 45-min warm ischemia in orthotopic liver transplantation (OLT). Donor and recipient rats were administered Y-27632 (3–30 mg/kg). Y-27632 treatment at 30 mg/kg in both donor and recipient prevented congestion of the grafted livers, as demonstrated by analysis of hemoglobin (Hb) content in the grafted livers, using in-vivo near-infrared spectroscopy. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hyaluronic acid at 4 h after OLT in the 30-mg/kg Y-27632-treated group were significantly lower than those in the control group. Specimens from the untreated control recipients showed sinusoidal congestion and massive fresh hepatocyte necrosis, whereas specimens from the Y-27632–treated recipients demonstrated minimal histological changes. Moreover, Y-27632 pre-treatment dramatically improved the survival of recipients. These results suggest that Y–27632 would be clinically useful for preventing liver failure associated with ischemia/reperfusion in liver transplantation.