Sinusoidal Microcirculation Changes After Small-for-size Liver Transplantation And Role Of Hepatic Stellate Cell On Microcirculation

Aim:Small-for-size graft injury is characterized by portal venous hyperperfusion and loss of intracellular homeostasis early after transplant.The long-term alteration of sinusoidal microcirculation and the auto-regulatory factor on graft function remain unknown.An experimental rat model of syngeneic liver transplantation with small-for-size and whole grafts was designed to examine:(1) whether microcirculatory disturbance recovers after portal pressure returns to baseline;(2) whether graft injury after liver transplantation leads to HSC activation with specific gene expression;(3) the response of sinusoidal auto-regulation to graft injury,especially after small-for-size liver transplantation;and(4) the role of different antagonist of ET receptor subtype on sinusoidal microcirculatory on small-for-size graft.Methods and method:An experimental rat model with small-for-size and whole grafts was designed. survival and portal pressure were detected.Sinusoidal microcirculation was examined by intravital fluorescence microscopy after each timepoint after transplantation.HSC activation-related protein expression was determined by real-time quantitative reverse-transcriptase polymerase chain reaction,Western blots and immunohistochemistry. Endothelin-1 and its receptors,and ultrastructural changes were also examined.Results:Although portal hypertension only persisted for 1 hour,a sustained microcirculatory hyper-hemodynamic state was accompanied by reduction of sinusoidal perfusion as well as elevation of sinusoidal diameter and number of apoptotic hepatocytes during the first 7 days.These resulted in lower survival rate and graft dysfunction.More hepatic stellate cells were subject to activation and transformation into myofibroblast-like cells from 1 day after transplantation.Serum endothelin-1 levels were significantly increased after transplantation,accompanied by over-expression of endothelin-1 A receptors on hepatic stellate cells.Sinusoidal derangement was attenuated by BQ-123,a antagonist of ETAR while no significant changes were showed in BQ-788 group.Conclusions:Small-for-size liver transplantation displayed progressive graft injury including long-term microcirculation disturbance,hepatocyte apoptosis and hepatic stellate cell activation,although portal hypertension transiently persisted for only 1 hour after reperfusion.Endothelin-1 might modulate sinusoidal microcirculation mostly by endothelin-1 A receptor-mediated hepatic stellate cell constriction in both nonperfused and perfused sinusoid with different effects.BQ-123,as a antagonist of ETAR could attenuate sinusoidal microcirculation by increasing the reperfusion rates,decreasing attenuate sinusoidal microcirculation by increasing the reperfusion rates,decreasing velocity and sinusoidal diameter rather than reducing hepatocytes apoptosis.However, BQ-788,which is a antagonist of ETBR didn't exert significant protective role on graft injuries.