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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

Authors

  • Kim R. Bridle,

    Corresponding author
    1. The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Envoi Specialist Pathologists and The Queensland Institute of Medical Research, Brisbane, Qld, Australia
    • Correspondence

      Dr Kim R Bridle

      The School of Medicine, University of Queensland

      Lower Lobby Level, Administration Building,

      Greenslopes Private Hospital,

      Greenslopes, Qld 4120, Australia

      Tel: 61 – 7 3346 0698

      Fax: 61 – 7 3847 6236

      e-mail: k.bridle@uq.edu.au

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    • These authors contributed equally to this manuscript.
  • Amy L. Sobbe,

    1. The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Envoi Specialist Pathologists and The Queensland Institute of Medical Research, Brisbane, Qld, Australia
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    • These authors contributed equally to this manuscript.
  • C. Erika de Guzman,

    1. The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Envoi Specialist Pathologists and The Queensland Institute of Medical Research, Brisbane, Qld, Australia
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  • Nishreen Santrampurwala,

    1. The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Envoi Specialist Pathologists and The Queensland Institute of Medical Research, Brisbane, Qld, Australia
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  • Lesley A. Jaskowski,

    1. The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Envoi Specialist Pathologists and The Queensland Institute of Medical Research, Brisbane, Qld, Australia
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  • Andrew D. Clouston,

    1. The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Envoi Specialist Pathologists and The Queensland Institute of Medical Research, Brisbane, Qld, Australia
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  • Catherine M. Campbell,

    1. The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Envoi Specialist Pathologists and The Queensland Institute of Medical Research, Brisbane, Qld, Australia
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  • V. Nathan Subramaniam,

    1. The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Envoi Specialist Pathologists and The Queensland Institute of Medical Research, Brisbane, Qld, Australia
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  • Darrell HG Crawford

    1. The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Envoi Specialist Pathologists and The Queensland Institute of Medical Research, Brisbane, Qld, Australia
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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.

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