The significance of hepatic stellate cell activation in small-for-size fatty liver graft injury

Abstract

Objective This study aims to investigate the significance of hepatic stellate cell activation at the early phase after liver transplantation using small-for-size fatty grafts with or without anti-inflammatory (FTY720) and/or anti-steatosis (adiponectin) therapy. Materials and Methods A rat orthotopic liver transplantation model using 60% of liver grafts was applied. Fatty Zucker rats (240-280 g) with 40% liver steatosis were used as donors. Lean Zucker rats (260-300 g) were used as recipients. Four groups of rats were included. In Group 1 (control group), no treatment was given. In Group 2 (FTY720 treatment group), FTY720 (1 mg/kg, IV) was administrated (1) at 20 minutes before graft harvesting in donors, (2) immediately before liver out in recipients, and (3) immediately after reperfusion in recipients. In Group 3 (adiponectin treatment group), adiponectin (1.5 mg/kg, IV) was given at 48 and 24 hours before graft harvesting in donors, and day 1 and day 2 posttransplantation. In Group 4 (combination therapy group), both FTY720 and adiponectin were given. Liver tissues were sampled at 6, 24 and 48 hours after reperfusion for the detection of hepatic stellate cell activation, intragraft protein expression of ET-1, VEGF and RhoA. Liver function and graft survival were also compared. Results FTY720 or adiponectin single treatment significantly improved 7-day graft survival rate from 0% (0/0) in the control group to 62.5% (5/8). It reached 100% (10/10) when combined with adiponectin and FTY720. The early and significant improvement of liver function was mainly found in the combination treatment group. Significant activation of hepatic stellate cells, which was detected by a-SMA staining, was found in the control group at 6, 24 and 48 hours after liver transplantation. Consistently, early and overexpression of ET-1 presented in the control group by immunostaining. Intragraft overexpression of VEGF and RhoA was also mainly found in the control group by Western-blot. Single and combination treatments attenuated the early activation of hepatic stellate cells accompanied with downregulation of ET-1, VEGF and RhoA during the first 48 hours after reperfusion. Conclusions Early and significant activation of hepatic stellate cells played an important role in smallfor-size fatty liver graft injury. Combination therapy of FTY720 plus adiponectin rescued small-for-size fatty liver grafts from injury in liver transplantation.