Effects Of Hepatic Ischemic Preconditioning On Hepatic Ischemia/Reperfusion Injury And Liver Regeneration And Its Protective Mechanisms

Objective:Hepatic ischemia/reperfusion (I/R) injury refers to an incredible phenomenon, which liver tissue reperfused will cause a series of more severe injuries. It is an inevitable injury in the liver surgery and liver transplant process. Liver transplantation is one of the most effective trewtments to end-stage liver disease. It is well-known that I/R injury is an important barrier to liver transplantation, which impairs remnant liver/ reduced-size-graft regeneration. Primary graft dysfunction and small-for-size syndrome are closely associated with I/R injury. The destructive damages are the result of a complex pathophysiological process with a number of contributory factors. Ischemic preconditioning (IPC) that consists of a brief period of liver ischemia followed by reperfusion has demonstrated organ-protection against a prolonged I/R injury including the improvement of the capacity for tissue cell proliferation. The simple surgical strategy to meet practical demands of liver resection lies in decreasing blood loss, impairing I/R injury, improving liver regeneration. IPC has been successively applied in diverse organs and shows a amount of potent protections. However, the effect of IPC on hepatic I/R injury and the potential mechanisms involved are not fully understood yet.Methods:Based on 50% and 70% hepatic ischemia and hemi-hepatotectomy models, we evaluated the effect of IPC, including biochemical and morphometric changes, reactive oxygen species (ROS) production and postischemic liver regeneration. The expressions of intercellular cell adhesion molecule-1 (ICAM-1) on the molecule and mRNA levels were assessed; the interactions between leukocyte and sinusoidal endothelial cell (SEC) in living animals were observed through intravital fluorescence microscopy. Furthermore, activation of mitogen-activated protein kinases (MAPKs), TNF-α, IL-6, phosphorylated c-Jun N-terminal kinase (p-JNK) and proliferating cell nuclear antigen (PCNA) was also investigated for understanding of the potential mechanism.Results:SEC is more sensitive to apoptosis induced by I/R injury compared to hepatocyte. IPC significantly alleviated postischemic liver function, decreased hepatic perfusion failure, production of reactive oxygen species and decreased numbers of adherent leukocytes, as well as improved I/R-induced hemodynamic disturbance as well. IPC downregulated the expression of ICAM-1 induced hepatic I/R injury. Insides, EPC significantly increased the expressions of PCNA, TNF-α, EL-6 and p-JNK.Conclusion:IPC attenuates hepatic I/R injury through suppression of the production of ROS and amelioration of postischemic microcirculatory disturbances. IPC enhances liver cell proliferation in the early phase by initiating ahead of schedule the reentry of cell cycle, which may be associated with the expression of p-JNK, the triggers of TNF-α/IL-6 signals.