- Dr. Yuan Zhai, Principal Investigator
- Dr. Jerzy Kupiec-Weglinski, Collaborator
- Dr. Genhong Cheng, Collaborator
- Dr. Xiuda Shen, Research Associate
- Dr. Bo Qiao, Research Associate
- University of California, Los Angeles, USA
- The Innate Immune Toll-Like-Receptor 4 Activation in Liver Ischemia/ Reperfusion Injury
Liver transplantation has been established as the definitive therapy for patients with end-stage liver disease. Ischemia/reperfusion injury (IRI) is an antigen (Ag)-independent inflammatory event, surrounding organ removal, storage and engraftment. It is not only critical to primary nonfunction or early dysfunction of liver transplants, but also plays an important role in the development of late liver dysfunction leading to chronic rejection. The mechanisms of liver injury following ischemia/reperfusion (I/R) are thought to involve a complex interaction of events initiated by host innate immunities that include Kupffer cell activation, cytokine release, neutrophil activation, increased expression of adhesion molecules, sinusoidal endothelial cell death, and hepatocyte apoptosis. Although the etiology of this post-transplant liver failure is multifactorial, a fundamental question remains to be addressed is what is the molecular nature of the initial innate immune activation leading to the full cascade of IRI.
This study aims at analyzing the Toll-like receptor (TLR) system and its role in initiating liver IRI, by focusing on both endogenous ligands generated during liver I/R, and downstream signaling pathways leading to the activation of effector mechanisms causing hepatocellular damages. TLR system is originally identified as the innate immune receptors in vertebrates to defend infectious agents. Increasing evidence indicates that vertebrates also utilize this sentinel system to distinguish well being from the disease in the absence of infections. Indeed, some intracellular proteins, and degraded cellular products have been shown to stimulate TLRs as endogenous ligands. Thus, results of this study will provide much needed in vivo evidence for the establishment of this new paradigm of innate immune functions in non-infectious diseases. This study should help to identify novel therapeutic targets for future clinical application to ameliorate IRI, which will not only improve the outcome of liver transplantation but also expand the organ donor pool (marginal donor more susceptible to IRI) available for transplantation.