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

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

Liver international : official journal of the International Association for the Study of the Liver (2014-02-13)
Kim R Bridle, Amy L Sobbe, C Erika de Guzman, Nishreen Santrampurwala, Lesley A Jaskowski, Andrew D Clouston, Catherine M Campbell, V Nathan Subramaniam, Darrell H G Crawford
ABSTRACT

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. 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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Ethanol solution, certified reference material, 2000 μg/mL in methanol
Sigma-Aldrich
Rapamycin, Ready Made Solution, 2.5 mg/mL in DMSO (2.74 mM), from Streptomyces hygroscopicus
Captopril for system suitability, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Ethyl alcohol, Pure, 190 proof, ACS spectrophotometric grade, 95.0%
Sigma-Aldrich
Captopril, meets USP testing specifications
Sigma-Aldrich
Captopril, ≥98% (HPLC), powder
Sigma-Aldrich
Ethyl alcohol, Pure, 200 proof, anhydrous, ≥99.5%
Irbesartan, European Pharmacopoeia (EP) Reference Standard
USP
Irbesartan, United States Pharmacopeia (USP) Reference Standard
Supelco
Irbesartan, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Ethanol, purum, absolute ethanol, denaturated with 4.8% isopropanol, A15 IPA1, ≥99.8% (based on denaturant-free substance)
Sigma-Aldrich
Ethanol, ACS reagent, prima fine spirit, without additive, F15 o1
Sigma-Aldrich
Irbesartan, ≥98% (HPLC), powder
Captopril, European Pharmacopoeia (EP) Reference Standard
Supelco
Captopril, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Ethyl alcohol, Pure, 160 proof, Excise Tax-free, Permit for use required
Supelco
Rapamycin, VETRANAL®, analytical standard
USP
Captopril, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Ethyl alcohol, Pure, 200 proof, for molecular biology
Sigma-Aldrich
Ethyl alcohol, Pure, 200 proof, meets USP testing specifications
Sigma-Aldrich
Ethyl alcohol, Pure, 200 proof, ACS reagent, ≥99.5%