Rapamycin as an inhibitor of hepatic fibrosis: relevance to whole blood levels

Popa, C., Bridle, K. R., Morgan, M. L., Clouston, A. D., Fletcher, L. M. and Crawford, D. H. G. (2008). Rapamycin as an inhibitor of hepatic fibrosis: relevance to whole blood levels. In: Journal of Hepatology: Abstracts of the 43rd Annual Meeting of the European Association for the Study of the Liver. 43rd Annual Meeting of the European Association for the Study of the Liver, Milan, Italy, (S177-S177). 23-27 April, 2008. doi:10.1016/S0168-8278(08)60467-5


Author Popa, C.
Bridle, K. R.
Morgan, M. L.
Clouston, A. D.
Fletcher, L. M.
Crawford, D. H. G.
Title of paper Rapamycin as an inhibitor of hepatic fibrosis: relevance to whole blood levels
Conference name 43rd Annual Meeting of the European Association for the Study of the Liver
Conference location Milan, Italy
Conference dates 23-27 April, 2008
Proceedings title Journal of Hepatology: Abstracts of the 43rd Annual Meeting of the European Association for the Study of the Liver   Check publisher's open access policy
Journal name Journal of Hepatology   Check publisher's open access policy
Place of Publication Ireland
Publisher Elsevier
Publication Year 2008
Sub-type Published abstract
DOI 10.1016/S0168-8278(08)60467-5
ISSN 0168-8278
Volume 48
Issue Suppl. 2
Start page S177
End page S177
Total pages 1
Language eng
Formatted Abstract/Summary
Background and Aims:
Chronic liver diseases are associated with fibrosis and cirrhosis and often lead to death. A key step in fibrogenesis is the PI3K-dependent activation of the mammalian target of rapamcyin (mTOR). In this study we aimed to investigate the antifibrotic potential of the mTOR inhibitor, rapamycin, in vitro and corroborate these findings in vivo in relation to whole blood rapamycin levels.

Methods:

Male Wistar rats were used to isolate hepatic stellate cells (HSCs) or induce hepatic fibrosis by bile-duct-ligation (BDL). Untreated BDL or sham-operated rats served as controls. Test rats received rapamycin at 1.5 mg/kg/day for 21 days. The expression levels of various markers of fibrosis were investigated and the mechanisms associated with antifibrotic activity were also examined.

Results:

Rapamycin has very potent antifibrotic effects both in vitro and in vivo. Of critical relevance is the finding that although BDL rats received a constant dose of rapamycin (1.5 mg/kg/day), the whole blood levels of rapamycin varied between 2.7 ng/ml and 37 ng/ml. Despite this, potent antifibrotic activity was demonstrated at all concentrations. In vivo, a 20 fold reduction in the procollagen type I mRNA (p = 0.0001) and reduced collagen protein deposition was observed in rapamycin-treated BDL rats. Similarly, rapamycin attenuated HSC activation as evidenced by reduced a-SMA protein expression (by 80%; p = 0.014) and inhibited markers of fibrosis including MMP2 mRNA (by 82.6%, p = 0.001), MMP9 mRNA (by 44%, p = 0.015) and TIMP1 mRNA (by 75.5%, p<0.0002) and protein (37%, p = 0.003) expression. Mechanistically, rapamycin inhibits p70s6 kinase (p = 0.004), a downstream mediator of mTOR, in a concentrationdependent manner and also has inhibitory effects on the TGFb signaling pathway.

Conclusions:
Our study suggests that low whole blood concentrations of rapamycin – as opposed to low administered dose – are effective at attenuating fibrosis in BDL rat livers. Given rapamycin’s side effect profile, and the variability in its metabolism, our results suggest that clinical trials should be designed to maintain low whole blood rapamycin levels which would not only be effective at inducing antifibrotic actions but may also limit side effects. 
Subjects 110307 Gastroenterology and Hepatology
Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status Unknown
Additional Notes Abstract number: 465

 
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Created: Fri, 19 Feb 2010, 15:32:05 EST by Ms Laura Mctaggart on behalf of Faculty Of Health Sciences