A successful approach to the therapy of hepatic injury and fibrosis should ideally involve the employment of inexpensive, non-toxic agents that will address rationally the pathophysiological processes that are responsible for the liver disease. At present no such agents are available in our standard therapeutic armamentarium. However, alternative therapeutic agents, in the form of herbal remedies, have been employed for generations in Asian countries in the treatment of liver diseases. Thus, our objective is to investigate the effectiveness of a number of herbal remedies, employing a rigorous scientific approach, to determine the relative effectiveness of these agents and the mechanisms by which they may be inhibiting liver injury and fibrosis. Specific Aims: 1) To determine the effectiveness of the herbal medicines in in vitro models of liver cell injury; and 2) to ascertain the effect of the herbal medicines on three models of liver injury and fibrosis. Methods: Hepatocytes and Kupffer cells from Osteogenic Disorder Shionogi (ODS) rats will be treated with ethanol, tert- butyl hydrogen peroxide (TBHP), or CC14 to characterize the injury and activation process. Mechanisms whereby herbal remedies inhibit this injury process will be explored by assays of lipid peroxidation, cytokine synthesis, tissue transglutaminase (tTG) expression, and NF-kappaB binding activity. Herbal remedies will also be employed to inhibit the injury and fibrosis induced by CC14 administration and bile duct ligation in in vivo systems, and the effectiveness of their action will be determined by histology and collagen protein determination, immunohistochemistry of tTG expression, and gel retardation assays of NF-kappaB activation. Health Relatedness: The successful use of one or more of the herbal agents in these models of liver injury and fibrogenesis will provide a rational basis for the use of these inexpensive, non-toxic agents in a series of clinical trials of liver disease in humans.
ethanol; protein glutamine gamma glutamyltransferase; laboratory mouse; laboratory rat; extracellular matrix; fibrosis; carbon tetrachloride poisoning; alternative medicine; immunocytochemistry; lipid peroxide; liver cell; Kupffer's cell; liver disorder; liver disorder chemotherapy; peroxidation; medicinal plant; plant extract; nonhuman therapy evaluation; cytotoxicity; oxidative stress; free radical scavenger; nuclear factor kappa beta