Alcohol and fibrogenesis.
In addition to fibrosis in response to necrosis and inflammation, alcohol may promote fibrogenesis directly, resulting in pericellular, perisinusoidal and perivenular fibrosis, in association with increased collagen mRNA. Acetaldehyde (produced in increased amounts because of the selective induction of cytochrome P450IIE1) stimulates collagen formation from either myofibroblasts, Ito cells or fibroblasts. One postulated mechanism is adduct formation of acetaldehyde with intracellular proteins, possibly stabilized by the NADH generated upon ethanol oxidation. The latter also increases lactate which might inhibit proline oxidase activity and increase available proline. During the initial stage of alcohol consumption, collagenase activity is increased, in keeping with enhanced collagen production. In later stages, however, there is a secondary decrease of collagenase activity; its deficiency relative to synthesis may also promote collagen deposition. In the early stage of alcohol induced fibrosis, collagens type I and type III accumulate, whereas later, type I predominates. Both can be formed in vitro by Ito cells, but cultured hepatocytes produce mainly type III. Immunohistochemical techniques revealed the deposition of type III procollagen in the extrahepatic collagen fibrils. Its degradation, as well as its enhanced synthesis, contribute to the appearance of procollagen III peptides in the blood. Their measurement by Fab fragments of the antibody is useful to assess the degree of fibrosis and to detect perivenular fibrosis, a precirrhotic lesion. In the baboon model, polyunsaturated lecithin was found to be effective in opposing alcohol-induced fibrosis.
Lieber
C S
CS
Alcohol Research and Treatment Center, Bronx VA Medical Center, New York.
D000437:Alcoholism / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D003094:Collagen / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology
D000431:Ethanol; D003094:Collagen