Rapamycin inhibits hepatic fibrosis in rats by attenuating multiple profibrogenic pathways

Abstract

Hepatic stellate cell transdifferentiation, epithelial-mesenchymal cell transition, and the ductular reaction each contribute to the development of hepatic fibrosis in cholestatic liver diseases. Inhibitors of mammalian target of rapamycin have antifibrotic properties. We evaluated the hypothesis that the antifibrotic action of rapamycin is due to attenuated myofibroblast proliferation in addition to an inhibitory effect on epithelial-mesenchymal transition and the ductular reaction. Hepatic fibrosis was induced by bile duct ligation, and rodents received 1.5 mg/kg/day rapamycin by subcutaneous infusion for 21 days. The expression of various markers of hepatic fibrosis, stellate cell transactivation, epithelial-mesenchymal transition, and the ductular reaction was compared between treated and untreated animals. Hepatic fibrosis, hepatic procollagen type 1 messenger RNA, and alpha-smooth muscle actin expression were significantly reduced in treated animals. Hepatic stellate cell procollagen expression and proliferation were also reduced by rapamycin. The following markers of epithelial-mesenchymal transition--vimentin protein expression, S100 calcium binding protein A4 and transforming growth factor beta 1 messenger RNA, and the mothers against decapentaplegic homolog signaling pathway--were all reduced after rapamycin treatment. The intensity of the ductular reaction was reduced by rapamycin as assessed by histopathological scoring and by reduced cytokeratin 19 expression. Rapamycin caused a reduction in hepatic progenitor cell proliferation. Together, these data show that multiple profibrogenic pathways are activated in an animal model of cholestasis and that rapamycin attenuates epithelial-mesenchymal transition and the ductular reaction as well as hepatic stellate cell activation.

Correction of glycogen storage disease type III with rapamycin in a canine model

“…The rapamycin-treated dogs had larger and softer livers than those of the untreated dogs which could be explained by less fibrosis-induced liver shrinkage. The anti-fibrotic effect of rapamycin was previously reported in several studies using a rat model of liver cirrhosis induced by bile duct ligation [23][24][25][26][27]. To our knowledge, this is the first report of rapamycin effect on liver fibrosis in a large animal model.…”

“…In vivo, rapamycin combined with recombinant human acid α-glucosidase (GAA) treatment improved glycogen clearance in the target tissue of adult GAA-KO mice; rapamycin alone increased phosphorylation (inactivation) of Gys and reduced glycogen accumulation in skeletal muscles of young GAA-KO mice [22]. Moreover, multiple studies have shown that rapamycin has a strong antifibrogenic effect on liver cirrhosis in rats that underwent bile duct ligation [23][24][25][26][27]. Based on these findings, we predicted that rapamycin could be a potential therapy for GSD III by limiting glycogen synthesis and preventing liver fibrosis.…”

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

“…7,25 However, mTOR is universally expressed regardless of cell types, so rapamycin was gradually used in anti-cancer and anti-fibrotic therapies. 11,26,27 We used N-and F-HLFs to demonstrate that rapamycin potently exerts direct profibrotic activities by promoting CCN2 expression in a Smad-independent and PI3K-dependent manner. In our sister paper, 28 we also showed rapamycin potentiates CCN2 expression in alveolar epithelial cells by PI3K pathway.…”

Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

“…A possible explanation could be that the balance between profibrotic and antifibrotic factors is shifted toward antifibrosis. 34 On the other hand, we did not measure Sirius red staining intensity but only measured the stained area, which in combination with cyst regression may also affect the results.…”