Neef M et al. (2006) Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis. J Hepatol 45: 786–796

The mammalian target of rapamycin (mTOR) activates hepatic stellate cells, which then produce extracellular matrix proteins in the fibrotic liver. Neef and colleagues investigated the effects of rapamycin, a potent inhibitor of mTOR, in two rat models of advanced liver cirrhosis.

Cirrhosis was induced in rats by either bile-duct ligation (BDL) (n = 89) or twice weekly 200 mg thioacetamide injections (n = 40). Eight control rats underwent sham BDL. Once cirrhosis was established, the rats were randomly allocated to receive 0.5 mg/kg body weight daily rapamycin, or no rapamycin, for either 14 or 28 days.

Rapamycin improved survival in BDL-treated cirrhotic rats (82% of rapamycin-treated versus 59% of rapamycin-untreated rats survived); by contrast, all the rats with thioacetamide-induced cirrhosis survived, irrespective of whether they received rapamycin. In both BDL and thioacetamide-induced cirrhosis, 14 days of rapamycin treatment prevented the accumulation of extracellular matrix proteins and suppressed interstitial matrix metalloproteinase 2 activity, which indicate preserved metabolic liver function. Rapamycin treatment for 28 days prolonged survival in rats with BDL-induced cirrhosis (but without beneficial effects on liver function); however, in rats with thioacetamide-induced cirrhosis, 28 days of rapamycin had no effect on liver function or fibrosis, compared with rapamycin-untreated rats.

The reduction in antifibrotic efficacy with time implies that compensatory mechanisms might reduce rapamycin's therapeutic value. The authors suggest that delay in the progression of cirrhosis might still be clinically useful, and propose that rapamycin should be evaluated as an antifibrotic drug in patients with cirrhosis.