Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term

• Published in: Journal of hepatology 2006-01, Vol.44 (1), p.167-175
• Main Authors: Neef, Markus, Ledermann, Monika, Saegesser, Hans, Schneider, Vreni, Widmer, Nicolas, Decosterd, Laurent Arthur, Rochat, Bertrand, Reichen, Juerg
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Benzamides; Bile duct-ligation; Biological and medical sciences; Biomarkers - metabolism; Collagen Type I - genetics; Collagen Type I - metabolism; Disease Progression; Experimental; Follow-Up Studies; Gastroenterology. Liver. Pancreas. Abdomen; Hepatic stellate cells; Imatinib; Imatinib Mesylate; Liver cirrhosis; Liver Cirrhosis, Experimental - drug therapy; Liver Cirrhosis, Experimental - metabolism; Liver Cirrhosis, Experimental - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Mass Spectrometry; Matrix Metalloproteinase 2 - metabolism; Medical sciences; Other diseases. Semiology; Piperazines - administration & dosage; Piperazines - pharmacokinetics; Piperazines - therapeutic use; Platelet-derived growth factor; Platelet-derived growth factor beta receptor; Procollagen - genetics; Procollagen - metabolism; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrimidines - administration & dosage; Pyrimidines - pharmacokinetics; Pyrimidines - therapeutic use; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Time Factors; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Treatment Outcome
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2005.06.015

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. BDL-rats were gavage fed with 20mg/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 α1(I) were measured by RT-PCR. Liver tissue concentration of imatinib was measured by tandem mass spectrometry. 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. 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.