title: Lack of efficacy of mTOR inhibitors and ACE pathway inhibitors as antifibrotic agents in evolving and established fibrosis in Mdr2⁻/⁻ mice.
abstract: OBJECTIVE
  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.
authors: 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.
authors: Kim R
authors: KR
authors: Bridle
authors: Amy L
authors: AL
authors: Sobbe
authors: C Erika
authors: CE
authors: de Guzman
authors: Nishreen
authors: N
authors: Santrampurwala
authors: Lesley A
authors: LA
authors: Jaskowski
authors: Andrew D
authors: AD
authors: Clouston
authors: Catherine M
authors: CM
authors: Campbell
authors: V
authors: V
authors: Nathan Subramaniam
authors: Darrell H G
authors: DH
authors: Crawford
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency* / Q000235:genetics; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D004359:Drug Therapy, Combination; D000068338:Everolimus / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D006909:Hydroxyproline / Q000378:metabolism; D000077405:Irbesartan; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013045:Species Specificity; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D002216:Captopril; D000068338:Everolimus; D006909:Hydroxyproline; D000077405:Irbesartan; D047428:Protein Kinase Inhibitors; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D013777:Tetrazoles; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C546843:mTOR protein, mouse
keywords: ACE inhibitors; Mdr2
  
  −/−; fibrosis; mTOR inhibitors