title: Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term.
abstract: OBJECTIVE
  Transactivated hepatic stellate cells (HSCs) represent the key source of extra cellular matrix (ECM) in fibrotic liver. Imatinib, a potent inhibitor of the PDGF receptor tyrosine kinase, reduces HSC proliferation and fibrogenesis when treatment is initiated before fibrosis has developed. We tested the antifibrotic potential of imatinib in ongoing liver injury and in established fibrosis.
  
  
  METHODS
  BDL-rats were gavage fed with 20 mg/kg/d imatinib either early (days 0-21) or late (days 22-35) after BDL. Untreated BDL-rats served as controls. ECM and activated HSCs were quantified by morphometry. Tissue activity of MMP-2 was determined by gelatin zymography. mRNA expression of TIMP-1 and procollagen alpha1(I) were measured by RT-PCR. Liver tissue concentration of imatinib was measured by tandem mass spectrometry.
  
  
  RESULTS
  Early imatinib reduced ECM formation by 30% (P=0.0455) but left numbers of activated HSCs and procollagen I expression unchanged. MMP-2 activity and TIMP-1 expression were reduced by 50%. Late imatinib treatment did not alter histological or molecular markers of fibrogenesis despite high imatinib tissue levels.
  
  
  CONCLUSIONS
  The antifibrotic effectiveness of imatinib is limited to the early phase of fibrogenesis. In ongoing liver injury other mediators most likely compensate for the inhibited PDGF effect.
authors.affiliation: Institute of Clinical Pharmacology, University of Berne, Berne, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Neef
authors.forename: Monika
authors.initials: M
authors.lastname: Ledermann
authors.forename: Hans
authors.initials: H
authors.lastname: Saegesser
authors.forename: Vreni
authors.initials: V
authors.lastname: Schneider
authors.forename: Nicolas
authors.initials: N
authors.lastname: Widmer
authors.forename: Laurent Arthur
authors.initials: LA
authors.lastname: Decosterd
authors.forename: Bertrand
authors.initials: B
authors.lastname: Rochat
authors.forename: Juerg
authors.initials: J
authors.lastname: Reichen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001549:Benzamides; D015415:Biomarkers / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005500:Follow-Up Studies; D000068877:Imatinib Mesylate; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D015415:Biomarkers; D024042:Collagen Type I; D010879:Piperazines; D011347:Procollagen; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D020778:Matrix Metalloproteinase 2