Rapamycin inhibits hepatic stellate cell proliferation in vitro and limits fibrogenesis in an in vivo model of liver fibrosis.
OBJECTIVE
The accelerated course of hepatic fibrosis that occurs in some patients after liver transplantation is a major clinical problem. This response may be caused by the antirejection therapeutics, and in an earlier report we showed that FK-506 enhanced the fibrogenic process in in vivo and in vitro models of liver fibrosis. In the present study, the aim was to determine whether a new immunosuppressive agent, rapamycin, enhances or inhibits liver fibrosis.


METHODS
Effects of rapamycin were investigated in a carbon tetrachloride model of hepatic fibrosis in rats and on hepatic stellate proliferation in vitro.


RESULTS
Rapamycin inhibited extracellular matrix deposition in the rat model of fibrogenesis as determined by histological analysis, collagen content, messenger RNA levels of procollagen and transforming growth factor beta1, and tissue transglutaminase activity. Moreover, rapamycin decreased platelet growth factor-induced proliferation of hepatic stellate cells.


CONCLUSIONS
These findings indicate that the new antirejection agent rapamycin inhibits hepatic fibrosis and thus may become a valuable addition to the immunosuppression armamentarium.
Zhu
J
J
Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Wu
J
J
Frizell
E
E
Liu
S L
SL
Bashey
R
R
Rubin
R
R
Norton
P
P
Zern
M A
MA
D000818:Animals; D002251:Carbon Tetrachloride; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D011503:Transglutaminases / Q000378:metabolism
D007166:Immunosuppressive Agents; D010982:Platelet-Derived Growth Factor; D011347:Procollagen; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003094:Collagen; D002251:Carbon Tetrachloride; D011503:Transglutaminases; D020123:Sirolimus