Immunotoxicology of host-response-mediated experimental liver injury

Abstract

Although inflammatory liver disease represents an ubiquitous human health problem, it can be managed pharmacologically in only a few cases. Symptomatic treatment is predominant while cure of hepatic dysfunction remains an elusive goal. There is no doubt that the development of new pharmacological therapies is limited by the availability of suitable animal or cellular models. Until the 1980's, drug development made use of experimental liver injury models commonly induced by xenobiotics such as carbon tetrachloride, bromobenzene, thioacetamide or dimethylnitrosamine, or by drugs like acetaminophen. These models of liver injury reflect only a minority of human liver disease. Human hepatic disorders are more frequently due to viral infections, septic complications or autoimmune processes. Therefore, models other than those using direct hepatotoxins, e.g. liver injury inducible by endotoxin (1) or tumor necrosis factor a (TNFa) (2) in galactosamine-sensitized mice or by the immunostimulatory lectin concanavalin A (3) represent a more promising experimental basis for the understanding of the hepatic mechanisms of inflammation, shock and autoimmunity. The first part of this review gives an account of general inflammatory and immune responses resulting in organ failure with special regard to liver disease. The second part discusses results obtained in experimental inflammatory liver injury models that provide mechanistic conclusions on the basis of the hepatoprotective potential of some established and some new drugs in vivo.