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Published on: January 7, 2019
Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term
Markus Neef1, Monika Ledermann, Hans Saegesser
1Institute of Clinical Pharmacology, University of Berne, Berne, Switzerland.
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.
Insights
Imatinib effectively reduces liver fibrosis markers when given early in injury, but not in established fibrosis. This suggests its antifibrotic potential is limited to the initial stages of liver disease.
Area of Science:
- Hepatology
- Fibrosis research
- Pharmacology
Background:
- Hepatic stellate cells (HSCs) drive liver fibrosis by producing extracellular matrix (ECM).
- Imatinib inhibits PDGF receptor tyrosine kinase, reducing HSC proliferation and fibrogenesis before fibrosis onset.
Purpose of the Study:
- To evaluate the antifibrotic effects of imatinib in ongoing liver injury and established liver fibrosis.
Main Methods:
- Rats underwent bile duct ligation (BDL) and received imatinib early (days 0-21) or late (days 22-35).
- Quantification of ECM, activated HSCs, MMP-2 activity, TIMP-1, and procollagen alpha1(I) mRNA expression.
- Imatinib tissue concentration measured by mass spectrometry.
Main Results:
- Early imatinib reduced ECM by 30% and MMP-2 activity/TIMP-1 expression by 50%, but did not alter HSC numbers or procollagen I.
- Late imatinib treatment showed no significant antifibrotic effects despite high drug levels.
Conclusions:
- Imatinib's antifibrotic efficacy is confined to the early phase of liver fibrogenesis.
- In established liver injury, compensatory mechanisms likely overcome PDGF inhibition.
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