ELEVATED PLASMA-LEVELS OF HYALURONIC-ACID INDICATE ENDOTHELIAL-CELL DYSFUNCTION IN THE INITIAL-STAGES OF ALCOHOLIC LIVER-DISEASE IN THE RAT

Background/Aims: We used the intragastric feeding rat model for alcoho lic liver disease to evaluate the relationship between morphologic and functional indicators of endothelial cell dysfunction. Methods: Twelv e groups of rats (4-5 rats/group) were fed the following diets: satura ted fat and dextrose (SD), saturated fat and ethanol (SE), corn oil an d dextrose (CD), corn oil and ethanol (CE). Four of the 12 groups were sacrificed at 2 weeks, four groups at 4 weeks and remaining four grou ps at 8 weeks. The following were evaluated at sacrifice: pathologic c hanges in the liver, endothelial cell proliferation using a monoclonal antibody to proliferating cell nuclear antigen, factor VIII-related a ntigen staining of endothelial cells in liver, plasma endotoxin, hyalu ronan and prostaglandin F-2 alpha. Results: Only CE rats at 4 and 8 we eks showed pathologic changes. The plasma levels of HA were significan tly higher in the CE groups compared to the other groups at all time i ntervals studied. In the CE rats, a significant correlation was obtain ed between plasma endotoxin and hyaluronan (r=0.84, p<0.01). Endotoxin levels also correlated significantly with the number of G(1)/S arrest ed hepatic sinusoidal endothelial cells (r=0.61, p<0.05). A role for p rostaglandin F-2 alpha, in causing endothelial dysfunction, was sugges ted by a significant correlation between plasma hyaluronan and prostag landin F-2 alpha levels (r=0.95, p<0.01). Positive factor VIII related antigen staining of hepatic endothelial cells was seen in rats with h igh plasma hyaluronan levels. Conclusion: We propose that endotoxin, m ediating part of its effect through prostaglandin F-2 alpha, plays a r ole in hepatic sinusoidal endothelial cell G(1)/S arrest. This morphol ogic change, associated with increased plasma hyaluronan levels, prece des capillarization in this model of alcoholic liver injury.