Hepatic fibrosis represents a major phenomena of chronic alcoholic liver disease. The major objective of this proposed is to delineate some of the fundamental mechanisms involved in this fibrotic response with special emphasis on specific aspects of collagen metabolism. The etiology of fibrosis will be examined with major emphasis on a recently identified fibrogenic factor found in CC14-damage rat liver and cirrhotic human liver. The parameters analyzed will be the rate of collagen synthesis, types of collagen produced and alterations in collagen production which occur when the fibrogenic factor is added to either hepatocyte and fibroblast cultures. The chemical properties of this fibrogenic factor will be determined with respect to chemical composition, oxidation-reduction state and quantities present in either normal or pathological tissue. It is hoped that complete elucidation of the chemical and biological properties of this fibrogenic factor may be helpful in explaining the aggressive nature of human alcoholic liver disease as it transcends from alcoholic hepatitis to cirrhosis. The complete characterization of hepatic liver collagen will also include analysis of collagenolytic systems which are active during the pathological process of hepatic fibrosis. Utilizing highly purified type I, III, IV and V collagen, radiolabeled with acetic anhydride, the degradation of specific types of collagen will be individually measured to differentiate specific enzyme systems in damaged hepatic tissue and specific changes in these activities during the pathological process. Further analysis of hepatic collagens including complete characterization of type IV, type V and the more recently identified unusual collagenous species such as the 7S complex, and the high molecular weight collagenous complex consisting of 45-55,000 mol wt subunits will be examined in normal and cirrhotic human liver. These less abundant collagen will be examined to the extent of amino acid composition, lysine and proline hydroxylation and glycosylation of hydroxylysine. While some of this is research currently under investigation in this laboratory, more detailed studies are needed to dilineate specific alterations in the various hepatic collagens at the molecular level.
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