Elevated plasma levels of hyaluronic acid indicate endothelial cell dysfunction in the initial stages of alcoholic liver disease in the rat.
OBJECTIVE
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 F2 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 G1/S arrested hepatic sinusoidal endothelial cell (r = 0.61, p < 0.05). A role for prostaglandin F2 alpha, in causing endothelial dysfunction, was suggested by a significant correlation between plasma hyaluronan and prostaglandin F2 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.


CONCLUSIONS
We propose that endotoxin, mediating part of its effect through prostaglandin F2 alpha, plays a role in hepatic sinusoidal endothelial cell G1/S arrest. This morphologic change, associated with increased plasma hyaluronan levels, precedes capillarization in this model of alcoholic liver injury.
Nanji
A A
AA
Department of Pathology, New England Deaconess Hospital, Boston MA 02215, USA.
Tahan
S R
SR
Khwaja
S
S
Yacoub
L K
LK
Sadrzadeh
S M
SM
D000818:Animals; D015415:Biomarkers / Q000097:blood*; D002453:Cell Cycle; D002455:Cell Division; D004041:Dietary Fats / Q000008:administration & dosage; D015237:Dinoprost / Q000097:blood; D004195:Disease Models, Animal; D004727:Endothelium / Q000378:metabolism / Q000473:pathology*; D004731:Endotoxins / Q000097:blood; D006820:Hyaluronic Acid / Q000097:blood*; D007118:Immunoassay; D007150:Immunohistochemistry; D008108:Liver Diseases, Alcoholic / Q000097:blood* / Q000473:pathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014841:von Willebrand Factor / Q000378:metabolism
D015415:Biomarkers; D004041:Dietary Fats; D004731:Endotoxins; D014841:von Willebrand Factor; D006820:Hyaluronic Acid; D015237:Dinoprost