Role of Eosinophils in Hepatic Ischemia Reperfusion Injury

PROJECT SUMMARY The goal of this proposal is to investigate the functional role of eosinophils in promoting tissue repair and regeneration after hepatic ischemia and reperfusion (IR) injury. Hepatic IR injury, which occurs during transplantation surgery, is a major factor contributing to acute liver dysfunction and long-term complications. Timely and robust liver repair and regeneration is vital to the resolution and recovery from ischemic liver damage. Thus, there is a critical need to identify key pro-reparative molecular and cellular mechanisms in order to develop therapeutic strategies to improve the outcomes of liver surgery and transplantation. Our preliminary data demonstrated that the peak of eosinophil accumulation in the liver after IR injury coincided with the critical time point of liver repair and regeneration. Eosinophil-deficient mice exhibited markedly delayed and impaired tissue repair after hepatic IR injury. In contrast, adoptive transfer of WT bone marrow-derived eosinophils (bmEos) to eosinophil-deficient mice dramatically improved liver repair to a similar rate and extent as in the WT mice. However, interleukin (IL)-4- and IL-13-deficient bmEos could not improve liver repair. We also found reduced EGFR activation and lower levels of HB-EGF in eosinophil-deficient mice. Together, these findings support our hypothesis that eosinophil-derived IL-4 and/or IL-13, through inducing HB-EGF production, play an essential role in promoting tissue repair after hepatic IR injury. We propose three Specific Aims to (1) Investigate the role of eosinophils in liver repair after IR injury, (2) Elucidate the mechanism by which eosinophils promote liver repair after IR injury, and (3) Explore the potential of targeting eosinophils to accelerate liver repair after IR injury.