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

Neef, Markus; Ledermann, M.; Saegesser, H.; Schneider, V.; Widmer, Nicolas; Décosterd, Laurent A.; Rochat, Bertrand; Reichen, Juerg

doi:10.1016/j.jhep.2005.06.015

Cited by 80 publications

(71 citation statements)

References 20 publications

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“…In addition, it had been shown in rodent models that PDGFR inhibitors are only effective against fibrosis if applied before injury 25,26 but do not revert already existing fibrosis. 27 These data are consistent with our results with mice lacking the binding site for PI3-kinase on PDGFR-b, which show a delayed proliferation in response to CCl 4 injury, as well as a weaker fibrotic response. The importance of the PI3K signaling pathway for the activation of hepatic stellate cells by PDGF has been demonstrated in vitro; 22 however, we show here for the first time that this pathway is also essential in vivo.…”

Section: Discussionsupporting

confidence: 92%

A gain-of-function mutation in the PDGFR-β alters the kinetics of injury response in liver and skin

Krampert

Heldin

Heuchel

2008

Laboratory Investigation

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Platelet-derived growth factor (PDGF) isoforms stimulate cell proliferation, migration and survival. We recently generated mice carrying a gain-of-function mutation within the activation loop of PDGF b-receptor (PDGFR-b D849N). Embryonic fibroblasts derived from these mice show elevated basal phosphorylation and altered kinetics for ligand-induced activation of PDGFR-b, as well as enhanced proliferation and migration. To investigate the effect of this mutation in vivo, we used carbon tetrachloride-induced liver injury as a model system. We observed a higher basal activation of mutant PDGFR-b in unchallenged livers; however, the difference in activation upon carbon tetrachloride stimulation was lower than expected, an effect that might be explained by a delayed response of the mutated receptor toward reactive oxygen species. Mutant mice showed enhanced proliferation of nonparenchymal liver cells and activation of hepatic stellate cells, leading to a small increase in early fibrosis formation. Another mouse strain lacking the binding site for phosphatidylinositol-3 0 kinase in PDGFR-b showed the reverse phenotype. These results suggest an important role for PDGFR-b signaling in the early injury-response. We confirmed this hypothesis with a second injury model, cutaneous wound healing, where we observed earlier proliferation and formation of granulation tissue in D849N-mutant mice.

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Section: Discussionsupporting

confidence: 92%

A gain-of-function mutation in the PDGFR-β alters the kinetics of injury response in liver and skin

Krampert

Heldin

Heuchel

2008

Laboratory Investigation

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“…This might potentially explain why PDGF antagonists in liver fibrosis were only effective when applied in the early stages. 32,33 We further found that the outcome of CCl 4 -induced liver fibrosis differs between individual rats (Supplementary Figure 4; Figure 5a). The degree of liver injury was previously believed to be proportional to the generation of the reactive metabolites of CCl 4 , but we now accept that the effects of biological responses to toxic injury, such as liver regeneration and tissue repair, determine the final toxic outcome.…”

Section: Pdgf Isoform Expression In Chronic Ccl4 Rat Livers E Borkhammentioning

confidence: 78%

Platelet-derived growth factor isoform expression in carbon tetrachloride-induced chronic liver injury

Borkham-Kamphorst

Коваленко

Roeyen

et al. 2008

Laboratory Investigation

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Platelet-derived growth factor (PDGF) has an essential role in liver fibrogenesis, as PDGF-B and -D both act as potent mitogens on culture-activated hepatic stellate cells (HSCs). Induction of PDGF receptor type-b (PDGFRb) in HSC is well documented in single-dose carbon tetrachloride (CCl 4 )-induced acute liver injury. Of the newly discovered isoforms PDGF-C and -D, only PDGF-D shows significant upregulation in bile duct ligation (BDL) models. We have now investigated the expression of PDGF isoforms and receptors in chronic liver injury in vivo after long-term CCl 4 treatment and demonstrated that isolated hepatocytes have the requisite PDGF signaling pathways, both in the naive state and when isolated from CCl 4 -treated rats. In vivo, PDGF gene expression showed upregulation of all PDGF isoforms and receptors, with values peaking at 4 weeks and decreasing to near basal levels by 8 and 12 weeks. Interestingly, PDGF-C increased significantly when compared to BDL-models. PDGF-A, PDGF-C and PDGF receptor type-a (PDGFRa) correlated closely with inflammation and steatosis. Immunohistochemistry revealed expression of PDGF-B, -C and -D in areas corresponding to centrilobular necrosis, inflammation and fibrosis, whereas PDGF-A localized in regenerative hepatocytes. PDGFRb was identified along the fibrotic septa, whereas PDGFRa showed positive staining in fibrotic septa and regenerative hepatocytes. Despite a significant decline of PDGF isoforms, hepatocyte regeneration peaked at 8 weeks. A marked difference in the degree of fibrosis was observed amongst the individual animals. In summary, PDGF expression in liver damage primarily parallels mesenchymal cell proliferation and extracellular matrix production, rather than hepatocyte regeneration. We conclude that PDGF levels in chronic liver injury peak at 4 weeks after onset of injury, and that the outcome of chronic toxic liver injury strongly depends on the individual capacity for tissue regeneration in the weeks following the peak of PDGF expression.

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“…First, therapies may address fibrosis-relevant pathways that are upregulated in these myofibroblasts, such as procollagen type I or other key structural components of the ECM, or block cellular receptors for ECM components and growth factors/chemokines that are upregulated upon fibrogenic activation. Current blockers of collagen synthesis have unwanted off-target effects, but inhibition of upstream fibrogenic signaling, e.g., PDGFRβ, a strong myofibroblast mitogen, with the tyrosine kinase inhibitor imatinib or a more specific PDGFRβ-blocking antibody retarded early but not advanced liver fibrogenesis (40,41).…”

Section: Figurementioning

confidence: 99%

Evolving therapies for liver fibrosis

Schuppan

Kim²

2013

J. Clin. Invest.

542

529

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Fibrosis is an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. With protracted damage, fibrosis can progress toward excessive scarring and organ failure, as in liver cirrhosis. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development, with enormous potential but also high risks. Preclinical research has yielded numerous targets for antifibrotic agents, some of which have entered early-phase clinical studies, but progress has been hampered due to the relative lack of sensitive and specific biomarkers to measure fibrosis progression or reversal. Here we focus on antifibrotic approaches for liver that address specific cell types and functional units that orchestrate fibrotic wound healing responses and have a sound preclinical database or antifibrotic activity in early clinical trials. We also touch upon relevant clinical study endpoints, optimal study design, and developments in fibrosis imaging and biomarkers.

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

Cited by 80 publications

References 20 publications

A gain-of-function mutation in the PDGFR-β alters the kinetics of injury response in liver and skin

A gain-of-function mutation in the PDGFR-β alters the kinetics of injury response in liver and skin

Platelet-derived growth factor isoform expression in carbon tetrachloride-induced chronic liver injury

Evolving therapies for liver fibrosis

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