Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis.
OBJECTIVE
Mammalian target of rapamycin (mTOR) signalling is central in the activation of hepatic stellate cells (HSCs), the key source of extracellular matrix (ECM) in fibrotic liver. We tested the therapeutic potential of the mTOR inhibitor rapamycin in advanced cirrhosis.


METHODS
Cirrhosis was induced by bile duct-ligation (BDL) or thioacetamide injections (TAA). Rats received oral rapamycin (0.5 mg/kg/day) for either 14 or 28 days. Untreated BDL and TAA-rats served as controls. Liver function was quantified by aminopyrine breath test. ECM and ECM-producing cells were quantified by morphometry. MMP-2 activity was measured by zymography. mRNA expression of procollagen-alpha1, transforming growth factor-beta1 (TGF-beta1) and beta2 was quantified by RT-PCR.


RESULTS
Fourteen days of rapamycin improved liver function. Accumulation of ECM was decreased together with numbers of activated HSCs and MMP-2 activity in both animal models. TGF-beta1 mRNA was downregulated in TAA, TGF-beta2 mRNA was downregulated in BDL. 28 days of rapamycin treatment entailed a survival advantage of long-term treated BDL-rats.


CONCLUSIONS
Low-dose rapamycin treatment is effectively antifibrotic and attenuates disease progression in advanced fibrosis. Our results warrant the clinical evaluation of rapamycin as an antifibrotic drug.
Neef
Markus
M
Institute of Clinical Pharmacology, University of Berne, Berne, Switzerland. neef@ikp.unibe.ch
Ledermann
Monika
M
Saegesser
Hans
H
Schneider
Vreni
V
Reichen
Juerg
J
D000284:Administration, Oral; D000632:Aminopyrine; D000818:Animals; D015153:Blotting, Western; D001944:Breath Tests / Q000379:methods; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000008:administration & dosage* / Q000627:therapeutic use; D015996:Survival Rate / Q000639:trends; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D053781:Transforming Growth Factor beta2 / Q000096:biosynthesis / Q000235:genetics; D016896:Treatment Outcome
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D000632:Aminopyrine; D020778:Matrix Metalloproteinase 2; D020123:Sirolimus