Molecular ablation of transforming growth factor β signaling pathways by tyrosine kinase inhibition: The coming of a promising new era in the treatment of tissue fibrosis

Rosenbloom, Joel; Jimenez, Sergio A.

doi:10.1002/art.23634

Cited by 26 publications

(17 citation statements)

References 29 publications

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“…Together, these data suggest that imatinib does not affect major functions of endothelial cells. The lack of vascular side effects of imatinib observed herein is supported by first case reports describing the use of imatinib in patients with SSc and related fibrosing disorders [5, 11, 12]. All patients reported in these case series experienced a strong regression of fibrosis and tolerated imatinib well.…”

Section: Discussionsupporting

confidence: 81%

Lack of inhibitory effects of the anti‐fibrotic drug imatinib on endothelial cell functions in vitro and in vivo

Venalis

Maurer

Akhmetshina

et al. 2009

J Cellular Molecular Medi

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Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by microangiopathy with progressive loss of capillaries and tissue fibrosis. Imatinib exerts potent anti-fibrotic effects and is currently evaluated in clinical trials. The aim of the present study was to exclude that the anti-fibrotic effects of imatinib are complicated by inhibitory effects on endothelial cell functions, which might augment vascular disease in SSc. Endothelial cells and mice were treated with pharmacologically relevant concentrations of imatinib. The expression of markers of vascular activation was assessed with real-time PCR. Proliferation was analysed with the cell counting experiments and the MTT assay. Apoptosis was quantified with caspase 3 assays, annexin V in vitro and with TUNEL staining in vivo. Migration was studied with scratch and transwell assays. Tube forming was investigated with the matrigel assay. Imatinib did not alter the expression of markers of vascular activation. Imatinib did not increase the percentage of annexin V positive cells or the activity of caspase 3. No reduction in proliferation or metabolic activity of endothelial cells was observed. Imatinib did not affect migration of endothelial cells and did not reduce the formation of capillary tubes. Consistent with the in vitro data, no difference in the number of apoptotic endothelial cells was observed in vivo in mice treated with imatinib. Imatinib does not inhibit activation, viability, proliferation, migration or tube forming of endothelial cells in vitro and in vivo. Thus, treatment with imatinib might not augment further endothelial cell damage in SSc.

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Section: Discussionsupporting

confidence: 81%

Lack of inhibitory effects of the anti‐fibrotic drug imatinib on endothelial cell functions in vitro and in vivo

Venalis

Maurer

Akhmetshina

et al. 2009

J Cellular Molecular Medi

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“…Results of these studies have provided novel approaches for the treatment and correction of the molecular alterations involved in the fibrotic component of SSc, among which the most promising appear to include modifiers of TGF-β1 activation and signaling, tyrosine kinase inhibitors, and inhibitors of other growth factors involved in the fibrotic process [48,51,150]. Many of these approaches have already been confirmed by extensive clinical and preclinical evidence and it is likely that they will be available for clinical use in the near future.…”

Section: Discussionmentioning

confidence: 99%

“…Other mechanisms of fine regulation include dephosphorylation of Smads through specific phosphatases as well as regulation of Smad nucleocytoplasmic shuttling and nuclear trapping. showing that activation of c-Abl induced by TGF-β is likely to contribute to the fibrosis and vasculopathy of the skin and internal organs in SSc [48]. One additional mechanism involving the c-Abl kinase has been implicated in the development of fibrosis in SSc.…”

Section: Growth Factorsmentioning

confidence: 99%

Role of Growth Factors in the Pathogenesis of Tissue Fibrosis in Systemic Sclerosis

Jimenez¹,

Castro²,

Piera-Velázquez

2010

CRR

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“…Whether imatinib mesylate or other tyrosine kinase inhibitors may be helpful in SSc patients with ILD remains currently unknown [64,65].…”

Section: Treatmentmentioning

confidence: 99%

Scleroderma Lung Disease

Pavec

Launay

Mathai

et al. 2010

Clinic Rev Allerg Immunol

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Pulmonary involvement is second in frequency only to esophageal involvement as a visceral complication of systemic sclerosis (SSc) and has surpassed renal involvement as the most common cause of death. Interstitial lung disease and pulmonary vascular disease, particularly pulmonary arterial hypertension, are the most commonly encountered types of lung involvement. Chronic aspiration, airway disease, neuromuscular weakness, extrinsic pulmonary restrictive pathology, pleural effusions, pneumothorax, and lung cancer cause clinically significant disease and occur commonly enough to be routinely considered in the assessment of the SSc patient with respiratory symptoms. Affected patients have a significantly worse prognosis than patients with SSc who are free of pulmonary involvement.

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Molecular ablation of transforming growth factor β signaling pathways by tyrosine kinase inhibition: The coming of a promising new era in the treatment of tissue fibrosis

Cited by 26 publications

References 29 publications

Lack of inhibitory effects of the anti‐fibrotic drug imatinib on endothelial cell functions in vitro and in vivo

Lack of inhibitory effects of the anti‐fibrotic drug imatinib on endothelial cell functions in vitro and in vivo

Role of Growth Factors in the Pathogenesis of Tissue Fibrosis in Systemic Sclerosis

Scleroderma Lung Disease

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