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 alcoholic liver disease to evaluate the relationship between morphologic and functional indicators of endothelial cell dysfunction. Methods: Twelve groups of rats (4-5 rats/group) were fed the following diets: saturated fat and dextrose (SD), saturated fat and ethanol (SE), corn oil and 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 groups at 8 weeks. The following were evaluated at sacrifice: pathologic changes in the liver, endothelial cell proliferation using a monoclonal antibody to proliferating cell nuclear antigen, factor VIII-related antigen staining of endothelial cells in liver, plasma endotoxin, hyaluronan and prostaglandin F-2 alpha. Results: Only CE rats at 4 and 8 weeks showed pathologic changes. The plasma levels of HA were significantly higher in the CE groups compared to the other groups at all time intervals studied. In the CE rats, a significant correlation was obtained between plasma endotoxin and hyaluronan (r=0.84, p<0.01). Endotoxin levels also correlated significantly with the number of G(1)/S arrested hepatic sinusoidal endothelial cells (r=0.61, p<0.05). A role for prostaglandin F-2 alpha, in causing endothelial dysfunction, was suggested by a significant correlation between plasma hyaluronan and prostaglandin 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 high plasma hyaluronan levels. Conclusion: We propose that endotoxin, mediating part of its effect through prostaglandin F-2 alpha, plays a role in hepatic sinusoidal endothelial cell G(1)/S arrest. This morphologic change, associated with increased plasma hyaluronan levels, precedes capillarization in this model of alcoholic liver injury.