Lack of efficacy of mTOR inhibitors and ACE pathway inhibitors as antifibrotic agents in evolving and established fibrosis in Mdr2-/- mice

Bridle, Kim R., Sobbe, Amy L., de Guzman, C. Erika, Santrampurwala, Nishreen, Jaskowski, Lesley A., Clouston, Andrew D., Campbell, Catherine M., Nathan Subramaniam, V. and Crawford, Darrell H. G. (2015) Lack of efficacy of mTOR inhibitors and ACE pathway inhibitors as antifibrotic agents in evolving and established fibrosis in Mdr2-/- mice. Liver International, 35 4: 1451-1463. doi:10.1111/liv.12494


Author Bridle, Kim R.
Sobbe, Amy L.
de Guzman, C. Erika
Santrampurwala, Nishreen
Jaskowski, Lesley A.
Clouston, Andrew D.
Campbell, Catherine M.
Nathan Subramaniam, V.
Crawford, Darrell H. G.
Title Lack of efficacy of mTOR inhibitors and ACE pathway inhibitors as antifibrotic agents in evolving and established fibrosis in Mdr2-/- mice
Formatted title
Lack of efficacy of mTOR inhibitors and ACE pathway inhibitors as antifibrotic agents in evolving and established fibrosis in Mdr2-/- mice
Journal name Liver International   Check publisher's open access policy
ISSN 1478-3231
1478-3223
Publication date 2015-04-01
Year available 2015
Sub-type Article (original research)
DOI 10.1111/liv.12494
Volume 35
Issue 4
Start page 1451
End page 1463
Total pages 13
Place of publication Malden, MA United States
Publisher Wiley-Blackwell Publishing
Collection year 2016
Language eng
Formatted abstract
Background & Aims
Mammalian target of rapamycin and angiotensin-converting enzyme inhibition has been shown to have antifibrotic activity in models of liver fibrosis. The aim of our study was to determine the efficacy of rapamycin, everolimus, irbesartan and captopril, alone and in combination, as antifibrotic agents in the Mdr2−/− model of cholestasis both in early injury and established disease.

Methods
Mdr2−/− mice were treated for 4 weeks with vehicle, rapamycin (1 mg/kg) or everolimus (5 mg/kg) every second day or with captopril (30 mg/kg/day), irbesartan (10 mg/kg/day) or vehicle. Further groups of 3-week-old Mdr2−/− mice were treated with rapamycin and irbesartan in combination (1 mg/kg/day and 10 mg/kg/day) or with rapamycin (2 mg/kg/day) for 4 weeks. Liver injury and fibrosis were compared between treated and untreated animals.

Results
There were no significant improvements in liver injury, histology, hepatic hydroxyproline or profibrogenic gene expression following treatment with rapamycin, everolimus, captopril or irbesartan at any time point studied. Likewise, there were no improvements in liver histology or profibrogenic gene expression following combination therapy or high-dose rapamycin treatment.

Conclusions
The antifibrotic effects of rapamycin, everolimus, captopril and irbesartan seen in other models of fibrosis were not replicated in the Mdr2−/− model in this study. This highlights the clear need to test specific antifibrotic agents in a number of different animal models. We believe this animal model is ideal to study usefulness of antifibrotic agents in cholestatic liver disease because of the similarity in genetics and hepatic histopathology to human cholestatic liver disease.
Keyword ACE inhibitors
Fibrosis
Mdr2 -/-
mTOR inhibitors
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
 
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