ROLE FOR TRANSFORMING GROWTH FACTOR-[BETA]1 IN INHIBITING ENDOTHELIAL-CELL PROLIFERATION IN EXPERIMENTAL ALCOHOLIC LIVER-DISEASE

We used the intragastric feeding rat model for alcoholic liver disease to investigate the relationship between transforming growth factor (T GF)-beta 1 and inhibition of endothelial cell proliferation, Twelve gr oups of male Wistar rats (four to five rats per group) were fed ethano l or dextrose with either corn oil or saturated fat for 1-, 2-, and 4- week, periods, All control animals were pair fed the same diets as eth anol-fed rats except that ethanol was isocalorically replaced by dextr ose, In the ethanol-fed groups, nonparenchymal cells were isolated and TGF-beta 1 was measured in the nonparenchymal cell supernatant. Liver pathology and endothelial cell proliferation with an antibody to prol iferating cell nuclear antigen were studied in all groups. Plasma TGF- beta 1 was measured in all rats, Pathological changes (fatty liver, ne crosis, and inflammation) were observed only in the corn oil/ethanol-f ed rats at 4 weeks. Significantly higher levels of TGF-beta 1 were see n in both plasma and nonparenchymal cell supernatant in rats fed corn oil and ethanol; plasma levels of TGF-beta 1 were not significantly di fferent between the dextrose-fed controls and saturated fat/ethanol-fe d rats. A significant inverse correlation (r = -0.89, P < 0.01) was se en between plasma TGF-beta 1 and the number of endothelial cells arres ted at G(1)/S. Immunohistochemistry revealed the presence of TGF-beta 1 staining in interstitial macrophages only in rats fed corn oil and e thanol, The present study provides evidence for a role for TGF-beta 1 in inhibiting endothelial cell proliferation in experimental alcoholic liver disease, Arrest of endothelial cells may had to their different iation and/or to produce mediators that could stimulate other cells su ch as Ito cells. Sustained TGF-beta 1 may also lead to Ito cell produc tion of extracellular matrix.