Kupffer cells (KC) constitute the largest population of fixed macrophages in the body. Although these cells play a critical role In the removal of particulates, cells and toxic substances, they can also release toxic mediators that may produce liver Injury. Agents that activate KC may potentiate the hepatotoxicity of other chemicals through an enhanced release of toxic mediators In response to minimal tissue injury. Recently, it has been shown that large doses of vitamin A (retinol) potentiate carbon tetrachloride induced liver injury. The mechanism by which vitamin A causes this potentiation is via Its ability to activate KC and perhaps other phagocytic cells. Upon damage to the hepatocytes by carbon tetrachloride (CCl4), the activated KC respond with an over production and release of reactive species of oxygen. These oxygen radicals promote peroxidation of hepatocyte lipids, an event associated with the dramatic potentiation in liver injury. These findings have led to the hypothesis. that modulation of KC function can alter the progression of chemical-induced liver injury. The overall goals of this research project are to better understand how modulation of KC function can Influence the liver's response to toxic chemicals and to elucidate an important mechanism by which one chemical potentiates the hepatotoxicity of another.
The specific aims are to: 1) more precisely characterize the potentiation of damage with respect to the dose and duration of treatment with vitamin A, and with the dose Of CCl4; determine if other retinoids cause this potentiation, and correlate these changes with the state of activation of KC; the contribution of neutrophils, other monocytes and lymphocytes to the potentiated response of chemical induced hepatic injury will also be evaluated; 2) to determine the role of oxygen radicals and lipid peroxidation in this potentiation as well as the degree to which superoxide dismutase, catalase and desferoximine block the potentiation; 3) to determine If vitamin A potentiates the hepatotoxicity of other environmental chemicals (CHCl3, cadmium, dichlorobenzene, among others) by a similar mechanism; 4) to develop in vitro systems for the co-culture of hepatocytes and KC to further define Interactions between these types upon chemical exposure, and 5) to determine if reactive oxygen species released from KC explains the susceptibility of Fischer-344 rats to 1,2-dichlorobenzene hepatotoxicity. The health implications of this work are significant since the opportunity for co-exposure to vitamin A and environmental hepatotoxicants Is very real. Secondly, with the current emphasis on the development of immunomodulatory drugs, it will be important to understand how modulation of immune cells such as KC can alter the response of target tissues to other chemicals (environmental pollutants, chemotherapeutic agents, etc.).
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