Ischemic preconditioning enhances regenerative capacity of hepatocytes in long‐term ischemically damaged rat livers

Abstract

Ischemic preconditioning (IPC) protects tissues against ischemia and reperfusion (I/R) injury. The aim of this study was to examine the impact of IPC on protection and regeneration of hepatocytes after prolonged I/R injury. A rat model of segmental (70%) hepatic ischemia was used to determine the effect of 10-min IPC preceding 40, 60, 90, or 120 min of liver ischemia. The effect was assessed by comparing cytolysis markers and necrotic areas of the liver, as well as the regenerative capacity of hepatocytes using the proliferating cell nuclear antigen labeling index (PCNA-LI) and weight of the ischemic liver lobe. Protein kinase B/Akt (Akt) and caspase-9 were investigated immunohistochemically to determine the effect of IPC on activation of survival and anti-apoptotic signals. In the model of 40 min I/R, which resulted in focal necrosis of the liver, IPC significantly protected against I/R injury by reducing the area of focal necrosis, level of PCNA-LI and immunoreactivities to Akt and caspase-9. In contrast, IPC did not prevent ischemic damage in the 90- and 120-min ischemic model with massive liver necrosis. However, IPC enhanced the regenerative capacity of the remaining hepatocytes with higher levels of PCNA-LI, number of Akt-positive cells and mean weight of the liver lobe postoperatively than in the controls. In a model of focal necrosis of the liver, IPC protected hepatocytes against I/R injury. In addition, in a model of massive necrosis, IPC maintained the regenerative capacity of the remaining hepatocytes by enhancing the survival signals.