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

Neef, Markus; Ledermann, Monika; Saegesser, Hans; Schneider, Vreni; Widmer, Nicolas; Decosterd, Laurent Arthur; Rochat, Bertrand; Reichen, Juerg (2006). Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term. Journal of hepatology, 44(1), pp. 167-75. Amsterdam: Elsevier 10.1016/j.jhep.2005.06.015

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BACKGROUND/AIMS: 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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Service Sector > Institute of Clinical Pharmacology and Visceral Research [discontinued]
UniBE Contributor:	Reichen, Jürg
ISSN:	0168-8278
ISBN:	16168515
Publisher:	Elsevier
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:45
Last Modified:	05 Dec 2022 14:14
Publisher DOI:	10.1016/j.jhep.2005.06.015
PubMed ID:	16168515
Web of Science ID:	000234445700027
URI:	https://boris.unibe.ch/id/eprint/18561 (FactScience: 753)