Inflammation is a critical component of the host response to injury and infection and is intimately tied to tissue repair and wound healing. Inflammatory mediators, such as the CXC chemokines, are essential in the response to hepatic injury. The CXC chemokines, including epithelial neutrophil activating protein (ENA-78) and macrophage inflammatory protein-2 (MIP-2), are induced by tumor necrosis factor-alpha (TNF) and are known for their neutrophil chemotactic and angiogenic properties. They are an important component of hepatic inflammation after liver injury. Some of the CXC chemokines contain a specific amino acid sequence at their amino terminal end, the ELR sequence (Glu-Leu-Arg); which define the molecule's biologic activity, specifically, neutrophil chemotaxis and angiogenesis. Other molecules in this family, including interferon-gamma- inducible protein (IP-10) and monokine induced by interferon-gamma (MIG), lack this sequence and therefore lack neutrophile chemotactic activity, are angiostatic, and inhibit angiogenesis induced ELR containing chemokines. Recent studies have demonstrated that the CXC chemokines have mitogenic effects in addition to causing angiogenesis and neutrophil chemotaxis. Experiments in our laboratory using a rat model of lobar hepatic ischemia/reperfusion have shown that TNF is released in response to hepatic ischemia/reperfusion. This TNF then triggers hepatic ENA-78 release, which is important for neutrophil influx and the development of inflammation in the injured liver. Interestingly, peak level of ENA-78 occurred at 24 hours of reperfusion, which is after the time of peak hepatic neutrophil influx. This observation, couple with the recently described angiogenic and mitogenic actions of the CXC chemokines, led us to postulate that ENA-78 was play an additional role in this model, possibly helping to initiate hepatic repair and regeneration. Our preliminary studies how that the ELR containing CXC chemokines, ENA-78 and MIP-2, cause hepatocyte proliferation. In contrast, the ELR negative molecules, IP-10 and MIG, do not induce hepatocyte proliferation. Further preliminary experiments suggests that the non-ELR containing CXC chemokines, ENA-78 and MIP-2, cause hepatocyte proliferation. In contrast, the ELR negative molecules, IP-10 and MIG, do not induce hepatocyte proliferation. Further preliminary experiments suggests that the non-ELR containing chemokines, IP-10 and MIG, inhibit hepatocyte proliferation induced by the ELR containing CXC chemokines. We propose that the ELR containing CXC chemokines are important not only for hepatic inflammation, but also for initiating lever regeneration after injury, which is crucial for host survival after an acute hepatic insult. We also propose that hepatic mitogenesis triggered by the ELR containing CXC molecules is inhibited by the non-ELR containing chemokines, and that the ELR motif is a critical region in these molecules for the induction of hepatic mitogenesis. Our laboratory has historically studied cytokines and the inflammatory response, particularly as they pertain to hepatic injury. This proposal is a logical extension of our previous studies involving the hepatic inflammatory responses as it begins to investigate the role of these inflammatory chemokines in the overall reparative process. This has potentially important clinical applications. The failing liver is the only vital organ for which we have no means of mechanical or pharmacological support. By providing insights into the hepatic regenerative process, these studies could potentially lead to novel treatments for the failing liver.
