The Protective Effect Of Mycophenolate Mofetil And Rapamycin On Hepatic Ischemia-reperfusion Injury And Its Mechanism

Objective:Hepatic ischemia/reperfusion(I/R) injury is one of the most common causes of early allograft dysfunction in liver transplanted patients and represents an additional risk factor for long-term survival after transplantation.The destructive effects of I/R injury are the result of a complex pathophysiological process with a number of contributory factors.Previous investigations have shown that overproduction of reactive oxygen species and hepatic microcirculation disturbances,which are characterized by capillary perfusion failure and increased leukocyte adherence,are important aspects of hepatic I/R injury.By targeting these aspects,the development of pharmaceutical strategies to attenuate hepatic I/R injury is important for achieving better clinical outcomes.Previous evidence has indicated that immunosuppressive drugs,which are inevitably used in transplantation,have impacts on organ I/R injury.Mycophenolate mofetil and rapamycin are powerful immunosuppressants that are currently used for the prevention of acute organ graft rejection.Earlier experimental studies on renal ischemia have suggested mycophenolate mofetil and rapamycin can inhibit the overexpression of adhesion molecules and suppress leukocyte-endothelial cell interactions,which play central roles in I/R injury.In recent years,mycophenolate mofetil and rapamycin have been gradually introduced into clinical liver transplantation as immunosuppressive drugs.Since transplanted livers are subject to I/R injury,the potential effects of mycophenolate mofetil and rapamycin on the process of hepatic I/R injury are of considerable importance.However,the effects of mycophenolate mofetil and rapamycin on hepatic I/R injury and the potential mechanisms involved are still not totally understood.Methods:Using rat liver ischemia-reperfusion injury model,the effects of mycophenolate mofetil and rapamycin were evaluated by assessing liver damage,production of reactive oxygen species,postischemic liver regeneration.Expression of vascular cell adhesion molecule-1(VCAM-1),intercellular cell adhesion molecule-1(ICAM-1),as well as leukocyte-endothelial cell interactions in both the rat hepatic microcirculation and isolated liver sinusoidal endothelial cells was observed by intravital fluorescence microscopy and cell culture.Furthermore,activation of mitogen-activated protein kinases(MAPKs) and mammalian target of rapamycin(mTOR) were also investigated for understanding of the potential mechanisms.Results:Liver cell apoptosis and overproduction of reactive oxygen species were decreased by mycophenolate mofetil and rapamycin pretreatment.Mycophenolate mofetil and rapamycin also improved I/R-induced hemodynamic turbulence,as evidenced by reduced hepatic perfusion failure and decreased numbers of rolling and adherent leukocytes.I/R injury induced activation of MAPKs and mTOR pathways as well as overexpressed ICAM-1 and VCAM-1 was downregulated by mycophenolate mofetil and rapamycin pretreatment.Conclusion:In summary,mycophenolate mofetil and rapamycin attenuate hepatic I/R injury through suppression of the production of reactive oxygen species and amelioration of postischemic microcirculatory disturbances.