The failing liver is the only vital organ for which we have no means of pharmacologic or mechanical support. The liver is also unique in that it can regenerate a normal functional cellular mass in response to many injuries, as opposed to most organs which repair themselves with non-functional scar. Liver failure is an important clinical problem that occurs after a variety of toxic, traumatic, and infectious insults. Liver failure also occasionally follows major hepatic resections for tumor. More importantly, hepatic resection is often precluded when a curative resection will leave an inadequate amount of functioning hepatic tissue, ultimately resulting in the death of the patient. Accidental and purposeful acetaminophen overdose accounts for 20 percent of acute liver failure cases in the U.S. Acetaminophen poisoning causes direct hepatocyte damage and patient survival relies heavily upon the liver's ability to recover from the damage and regenerate. Acetaminophen-induced liver injury is well characterized, however, the mechanisms of liver protection, repair, and regeneration have not been fully examined. This proposal examines a specific cytokine, stem cell factor (SCF), in hepatocyte protection and regeneration during acetaminophen-induced liver toxicity, as well as following 70 percent hepatectomy. SCF is well-known as an important leukocyte hematopoietic factor, involved in the proliferation and maturation of multiple leukocyte subsets, especially mast cells. More recently, it has been shown to be an important factor in the development of normal structural cells, such as hepatocytes. We will utilize two murine models, acetaminophen poisoning and 70 percent hepatectomy, to investigate SCF's effects following liver injury. We hypothesize that SCF functions via two mechanisms, having anti-apoptotic protective effects, as well as enhancing the hepatocyte regenerative response. To test this postulate, we will focus on mechanisms of SCF-associated liver repair utilizing the following specific aims: 1) To examine the expression, production, and cellular source of hepatic SCF following 70 percent hepatectomy or acetaminophen-induced injury, 2) To examine the regulation of transmembrane versus soluble SCF and its receptor, c-kit, in the setting of toxic or traumatic hepatic injury, 3) To investigate SCF's effects and mechanism(s) of action on hepatocyte apoptosis and proliferation after toxic or traumatic hepatic injury, and 4) To investigate the interactions of SCF and IL-6 in the liver's recovery from toxic or traumatic injury. These studies will help to elucidate novel mechanisms in SCF-mediated hepatocyte protection and regeneration in a clinically relevant liver resection and toxicity model.
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