Treatment of pulmonary fibrosis in systemic sclerosis: Light at the end of the tunnel?

Wollheim, Frank A.

doi:10.1002/art.22315

Cited by 14 publications

(6 citation statements)

References 22 publications

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“…21 Although inflammation is a prominent early finding in fibrosing conditions that might contribute to both triggering and sustaining the fibrotic process, therapeutic agents targeting the inflammatory response such as corticosteroids generally fail to reverse or slow the progression of fibrosis, and are primarily ineffective in SSc. 22 In the present studies, rosiglitazone attenuated the early cutaneous inflammation induced by bleomycin, consistent with the recognized inhibitory effects of PPAR-␥ on immune and inflammatory responses. 23 The mechanistic basis for the anti-inflammatory effects of PPAR-␥ remains incompletely understood.…”

Section: Discussionsupporting

confidence: 66%

Rosiglitazone Abrogates Bleomycin-Induced Scleroderma and Blocks Profibrotic Responses Through Peroxisome Proliferator-Activated Receptor-γ

Melichian

Chang

et al. 2009

The American Journal of Pathology

210

203

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The nuclear hormone receptor , peroxisome proliferator-activated receptor (PPAR)-␥ , originally identified as a key mediator of adipogenesis , is expressed widely and implicated in diverse biological responses. Both natural and synthetic agonists of PPAR-␥ abrogated the stimulation of collagen synthesis and myofibroblast differentiation induced by transforming growth factor (TGF)-␤ in vitro. To characterize the role of PPAR-␥ in the fibrotic process in vivo, the synthetic agonist rosiglitazone was used in a mouse model of scleroderma. Rosiglitazone attenuated bleomycin-induced skin inflammation and dermal fibrosis as well as subcutaneous lipoatrophy and counteracted the up-regulation of collagen gene expression and myofibroblast accumulation in the lesioned skin. Rosiglitazone treatment reduced the induction of the early-immediate transcription factor Egr-1 in situ without also blocking the activation of Smad2/3. In both explanted fibroblasts and skin organ cultures, rosiglitazone prevented the stimulation of collagen gene transcription and cell migration elicited by TGF-␤. Rosiglitazone-driven adipogenic differentiation of both fibroblasts and preadipocytes was abrogated in the presence of TGF-␤; this effect was accompanied by the concomitant down-regulation of cellular PPAR-␥ mRNA expression. Collectively, these results indicate that rosiglitazone treatment attenuates inflammation, dermal fibrosis, and subcutaneous lipoatrophy via PPAR-␥ in a mouse model of scleroderma and suggest that pharmacological PPAR-␥ ligands, widely used as insulin sensitizers in the treatment of type-2 diabetes mellitus, may be potential therapies for scleroderma. (Am J Pathol

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Section: Discussionsupporting

confidence: 66%

Rosiglitazone Abrogates Bleomycin-Induced Scleroderma and Blocks Profibrotic Responses Through Peroxisome Proliferator-Activated Receptor-γ

Melichian

Chang

et al. 2009

The American Journal of Pathology

210

203

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“…The cases reported by Kay and High showed substantial clinical improvement as well as histopathological evidence of reduction of collagen biosynthesis following treatment with imatinib. These four papers provide valuable information regarding the novel role of c-Abl in tissue fibrosis and, more importantly, bring closer the promise of “light at the end of the tunnel” for patients affected by these diseases as stated in a recent editorial by Wolheim (23). …”

Section: The Light At the End Of The Tunnel For Patients With Systemimentioning

confidence: 91%

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

Rosenbloom¹,

Jimenez²

2008

Arthritis & Rheumatism

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“…IgG isolated from SSc patients has been shown to induce PDGFR tyrosine phosphorylation, to increase the production of reactive oxygen species (ROS), and to stimulate collagen production by fibroblasts in vitro. Based on these data and on the demonstration that PDGF and TGF␤ are important mediators of fibrosis in different models, imatinib mesylate has been suggested as a rational treatment of SSc (11)(12)(13). This potent tyrosine kinase inhibitor is selective for PDGFR and Abl, which may be involved in TGF␤ signaling and in fibrosis (14).…”

mentioning

confidence: 99%

Lack of evidence of stimulatory autoantibodies to platelet‐derived growth factor receptor in patients with systemic sclerosis

Classen¹,

Henrohn²,

Rorsman³

et al. 2009

Arthritis & Rheumatism

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Objective. Systemic sclerosis (SSc) is a severe connective tissue disease of unknown etiology, characterized by fibrosis of the skin and multiple internal organs. Recent findings suggested that the disease is driven by stimulatory autoantibodies to platelet-derived growth factor receptor (PDGFR), which stimulate the production of reactive oxygen species (ROS) and collagen by fibroblasts. These results opened novel avenues of research into the diagnosis and treatment of SSc. The present study was undertaken to confirm the presence of anti-PDGFR antibodies in patients with SSc.Methods. Immunoglobulins from 37 patients with SSc were purified by protein A/G chromatography. PDGFR activation was tested using 4 different sensitive bioassays, i.e., cell proliferation, ROS production, signal transduction, and receptor phosphorylation; the latter was also tested in a separate population of 7 patients with SSc from a different research center.Results. Purified IgG samples from patients with SSc were positive when tested for antinuclear autoantibodies, but did not specifically activate PDGFR␣ or PDGFR␤ in any of the tests. Cell stimulation with PDGF itself consistently produced a strong signal.Conclusion. The present results raise questions regarding the existence of agonistic autoantibodies to PDGFR in SSc.

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Treatment of pulmonary fibrosis in systemic sclerosis: Light at the end of the tunnel?

Cited by 14 publications

References 22 publications

Rosiglitazone Abrogates Bleomycin-Induced Scleroderma and Blocks Profibrotic Responses Through Peroxisome Proliferator-Activated Receptor-γ

Rosiglitazone Abrogates Bleomycin-Induced Scleroderma and Blocks Profibrotic Responses Through Peroxisome Proliferator-Activated Receptor-γ

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

Lack of evidence of stimulatory autoantibodies to platelet‐derived growth factor receptor in patients with systemic sclerosis

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