Progressive Transforming Growth Factor β1–induced Lung Fibrosis Is Blocked by an Orally Active ALK5 Kinase Inhibitor

Bonniaud, Philippe; Margetts, Peter J.; Kolb, Martin; Schroeder, Jane Ann; Kapoun, Ann M.; Damm, Debby; Murphy, Alison; Chakravarty, Sarvajit; Dugar, Sundeep; Higgins, Linda S.; Protter, Andrew A.; Gauldie, Jack

doi:10.1164/rccm.200405-612oc

Cited by 228 publications

(159 citation statements)

References 41 publications

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“…TGF-␤ is one of the major targets in the development of antifibrotic therapies for pulmonary fibrosis, and a number of experimental studies in animals strongly support this approach (34,35). In our model, we induced severe and homogenous bilateral fibrosis of the visceral pleura, leading to significant restriction of lung volumes.…”

Section: Discussionmentioning

confidence: 94%

TGF-β1 Induces Progressive Pleural Scarring and Subpleural Fibrosis

Decologne

Kolb

Margetts

et al. 2007

The Journal of Immunology

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113

119

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Pleural fibrosis is a misunderstood disorder which can cause severe restrictive lung disease with high morbidity and even mortality. The condition can develop in response to a large variety of diseases and tissue injury, among them infectious disease, asbestos, drugs, and radiation therapy. There is no efficient treatment to reverse established pleural fibrosis. TGF-β1 is suspected, even if not proven, as a key cytokine in this process. In this study, we used adenoviral gene transfer of TGF-β1 to the pleural mesothelium in rats. We show that local and transient TGF-β1 overexpression induces homogenous, prolonged, and progressive pleural fibrosis without pleurodesis, associated with severe impairment of pulmonary function. We further demonstrate that pleural fibrosis can expand into the lung parenchyma from the visceral layer, but not into the muscle from the parietal layer. We provide evidence that matrix accumulation and fibrosis within the parenchyma evolved through a process involving “mesothelial-fibroblastoid transformation” and suggest that the pleural mesothelial cell may be an important player involved in the development of the subpleural distribution pattern known to be a hallmark of pulmonary fibrosis. This new model of pleural fibrosis will allow us to better understand the mechanisms of progressive fibrogenesis, and to explore novel antifibrotic therapies in the pleural cavity.

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Section: Discussionmentioning

confidence: 94%

TGF-β1 Induces Progressive Pleural Scarring and Subpleural Fibrosis

Decologne

Kolb

Margetts

et al. 2007

The Journal of Immunology

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113

119

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“…47 In a rat model of pulmonary fibrosis triggered by adenovirus-mediated gene transfer of active TGF␤1, a TGF␤ receptor I inhibitor blocked both fibrotic induction and progression. 48 Transient gene transfer and expression of Smad7 or decorin, both negative regulators of TGF␤, prevented bleomycin-induced lung fibrosis in mice. 49,50 There have been several studies of myofibroblast differentiation in response to photorefractive keratectomy (PRK) in which anti-TGF␤ antibodies have been applied directly to the ocular surface of rabbits or cats.…”

Section: Discussionmentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

Lehmann

Xia

Kulkarni

et al. 2011

The American Journal of Pathology

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Fibrosis can occur in any human tissue when the normal wound healing response is amplified. Such amplification results in fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix deposition. Occurrence of these sequelae in organs such as the eye or lung can result in severe consequences to health. Unfortunately, medical treatment of fibrosis is limited by a lack of safe and effective therapies. These therapies may be developed by identifying agents that inhibit critical steps in fibrotic progression; one such step is myofibroblast differentiation triggered by transforming growth factor-␤1 (TGF␤1). In this study, we demonstrate that TGF␤1-induced myofibroblast differentiation is blocked in human fibroblasts by a candidate endogenous aryl hydrocarbon receptor (AhR) ligand 2-(1=H-indole-3=-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Our data show that ITE disrupts TGF␤1 signaling by inhibiting the nuclear translocation of Smad2/3/4. Although ITE functions as an AhR agonist, and biologically persistent AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, cause severe toxic effects, ITE exhibits no toxicity. Interestingly, ITE effectively inhibits TGF␤1-driven myofibroblast differentiation in AhR ؊/؊ fibroblasts: Its ability to inhibit TGF␤1 signaling is AhR independent. As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent.

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“…Therefore, inhibition of TGF-β signaling was intensively studied to evaluate the effi ciency of antifi brotic therapies. Positive eff ects on fi brosis of therapies targeting TGF-β pathways were found (Bonniaud et al, 2005;de Gouville and Huet, 2006). Another profi brotic cytokine, IL-13, is a T-helper type 2 cytokine; it can stimulate the production of fi broblast collagen independently from TGF-β (Kolodsick et al, 2004).…”

Section: Tablementioning

confidence: 99%

Effects of simvastatin on bleomycin-induced pulmonary fibrosis in female rats

et al. 2012

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Statins reduce cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase and have a major place in the treatment of atherosclerotic disease. Recent studies have shown anti-infl ammatory properties of statins. The purpose of this study was to evaluate the anti-infl ammatory eff ect of simvastatin on bleomycin (BLM)-induced pulmonary fi brosis in rats. A total of 31 female Sprague-Dawley rats were divided into four groups: (1) intratracheal (IT) phosphate-buff ered saline (PBS) + intraperitoneal (IP) PBS (n=7); (2) IT BLM + IP PBS (n=8); (3) IT BLM + low dose (LD) simvastatin (1 mg/kg daily, n=8); (4) IT BLM + high dose (HD) simvastatin (5 mg/kg daily, n=8). Simvastatin was administered IP for 15 days, beginning 1 day prior to IT BLM. The eff ect of simvastatin on pulmonary fi brosis was studied by measurements of IL-13, PDGF, IFN-γ, TGF-β1 levels in bronchoalveolar lavage (BAL) fl uid and lung tissue hydroxyproline (HPL) content and by histopathological examination (Ashcroft score). BLM caused signifi cant change in BAL fl uid cytokine levels and increased both HPL content and histopathological score (p<0.001 for all). While LD simvastatin had no eff ect on cytokine levels, HD signifi cantly reduced IL-13 (15.12 ±7.08 pg/ml vs. 4.43±2.34 pg/mL; p<0.05) and TGF-β1 levels (269.25 ±65.42 pg/mL vs. 131.75±32.65 pg/mL; p<0.05). Neither HD nor LD simvastatin attenuated HPL content or Ashcroft score. In conclusion, this study showed that LD simvastatin had no eff ect on a BLMinduced pulmonary fi brosis model, while the high dose caused partial improvement in profi brotic cytokine levels.

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Progressive Transforming Growth Factor β1–induced Lung Fibrosis Is Blocked by an Orally Active ALK5 Kinase Inhibitor

Cited by 228 publications

References 41 publications

TGF-β1 Induces Progressive Pleural Scarring and Subpleural Fibrosis

TGF-β1 Induces Progressive Pleural Scarring and Subpleural Fibrosis

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

Effects of simvastatin on bleomycin-induced pulmonary fibrosis in female rats

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