The effect of nintedanib compared to pirfenidone on proliferation of lung fibroblasts from patients with IPF

Schuett, Jennifer; Ostermann, Angela; Wollin, Lutz

doi:10.1183/13993003.congress-2015.pa3846

Cited by 3 publications

(3 citation statements)

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“…The anti-fibrotic and anti-inflammatory effects of pirfenidone have not been fully established [51]. Some studies have shown that pirfenidone had a direct effect on fibroblasts, whereas others indicated that the effect was very weak [49,[52][53][54][55]. However, these studies were performed for a shorter period of 1-2 days which may influence the effect on protein synthesis, as indicated by our results.…”

Section: Discussionmentioning

confidence: 62%

Prolonged Scar-in-a-Jar: an in vitro screening tool for anti-fibrotic therapies using biomarkers of extracellular matrix synthesis

et al. 2020

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Background: Idiopathic pulmonary fibrosis (IPF) is a rapidly progressing disease with challenging management. To find novel effective therapies, better preclinical models are needed for the screening of anti-fibrotic compounds. Activated fibroblasts drive fibrogenesis and are the main cells responsible for the accumulation of extracellular matrix (ECM). Here, a prolonged Scar-in-aJar assay was combined with clinically validated biochemical markers of ECM synthesis to evaluate ECM synthesis over time. To validate the model as a drug screening tool for novel antifibrotic compounds, two approved compounds for IPF, nintedanib and pirfenidone, and a compound in development, omipalisib, were tested. Methods: Primary human lung fibroblasts from healthy donors were cultured for 12 days in the presence of ficoll and were stimulated with TGF-β1 with or without treatment with an ALK5/TGF-β1 receptor kinase inhibitor (ALK5i), nintedanib, pirfenidone or the mTOR/PI3K inhibitor omipalisib (GSK2126458). Biomarkers of ECM synthesis were evaluated over time in cell supernatants using ELISAs to assess type I, III, IV, V and VI collagen formation (PRO-C1, PRO-C3, PRO-C4, PRO-C5, PRO-C6), fibronectin (FBN-C) deposition and α-smooth muscle actin (α-SMA) expression. Results: TGF-β1 induced synthesis of PRO-C1, PRO-C6 and FBN-C as compared with unstimulated fibroblasts at all timepoints, while PRO-C3 and α-SMA levels were not elevated until day 8. Elevated biomarkers were reduced by suppressing TGF-β1 signalling with ALK5i. Nintedanib and omipalisib were able to reduce all biomarkers induced by TGF-β1 in a concentration dependent manner, while pirfenidone had no effect on α-SMA. Conclusions: TGF-β1 stimulated synthesis of type I, III and VI collagen, fibronectin and α-SMA but not type IV or V collagen. Synthesis was increased over time, although temporal profiles differed, and was modulated pharmacologically by ALK5i, nintedanib, pirfenidone and omipalisib. This prolonged 12-day Scar-in-aJar assay utilising biochemical markers of ECM synthesis provides a useful screening tool for novel anti-fibrotic compounds.

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Section: Discussionmentioning

confidence: 62%

Prolonged Scar-in-a-Jar: an in vitro screening tool for anti-fibrotic therapies using biomarkers of extracellular matrix synthesis

et al. 2020

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“…Activated interstitial fibroblasts are the key effector cells in the pathogenesis of fibrosing ILDs. Nintedanib inhibits fibroblast proliferation induced by stimuli such as PDGF, FGF, VEGF [42, 43] and serum [44]. Nintedanib has also been shown to reduce the motility of lung fibroblasts from patients with IPF [45] and to inhibit the contraction of human lung fibroblasts in collagen gels stimulated with PDGF [46].…”

Section: Mechanisms Of Action Of Nintedanib In Pulmonary Fibrosismentioning

confidence: 99%

Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases

et al. 2019

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A proportion of patients with fibrosing interstitial lung diseases (ILDs) develop a progressive phenotype characterised by decline in lung function, worsening quality of life and early mortality. Other than idiopathic pulmonary fibrosis (IPF), there are no approved drugs for fibrosing ILDs and a poor evidence base to support current treatments. Fibrosing ILDs with a progressive phenotype show commonalities in clinical behaviour and in the pathogenic mechanisms that drive disease worsening. Nintedanib is an intracellular inhibitor of tyrosine kinases that has been approved for treatment of IPF and has recently been shown to reduce the rate of lung function decline in patients with ILD associated with systemic sclerosis (SSc-ILD). In vitro data demonstrate that nintedanib inhibits several steps in the initiation and progression of lung fibrosis, including the release of pro-inflammatory and pro-fibrotic mediators, migration and differentiation of fibrocytes and fibroblasts, and deposition of extracellular matrix. Nintedanib also inhibits the proliferation of vascular cells. Studies in animal models with features of fibrosing ILDs such as IPF, SSc-ILD, rheumatoid arthritis-ILD, hypersensitivity pneumonitis and silicosis demonstrate that nintedanib has anti-fibrotic activity irrespective of the trigger for the lung pathology. This suggests that nintedanib inhibits fundamental processes in the pathogenesis of fibrosis. A trial of nintedanib in patients with progressive fibrosing ILDs other than IPF (INBUILD) will report results in 2019.

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“…1). In human lung fibroblasts, nintedanib inhibited fibroblast proliferation (including migration of fibrocytes and fibrocyte-induced fibroblast proliferation), growth factor-stimulated fibroblast motility and contraction, and TGF-binduced fibroblast to myofibroblast transformation [31][32][33][34][35][36][37]. In addition, nintedanib reduced TGF-b-induced deposition of collagen and upregulated secretion of pro-matrix metalloproteinase 2 while downregulating its inhibitor, suggesting increased degradation of the ECM [31].…”

Section: Nintedanibmentioning

confidence: 99%

Therapeutic targets in idiopathic pulmonary fibrosis

Kolb

Bonella

Wollin

2017

Respiratory Medicine

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Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease. After many drugs failed in clinical trials, improvements in the understanding of the pathogenesis of IPF led to the approval of two drugs that slow the progression of the disease. However, the prognosis for patients with IPF remains poor and the search continues for drugs that inhibit the pathogenic pathways active in IPF to reduce or even halt the progression of the disease. In this article, we review the mechanisms of action of the two approved therapies for IPF (nintedanib and pirfenidone) and of the investigational compounds that are in Phase II trials and discuss the potential for combination therapy in the treatment of IPF.

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The effect of nintedanib compared to pirfenidone on proliferation of lung fibroblasts from patients with IPF

Cited by 3 publications

References 0 publications

Prolonged Scar-in-a-Jar: an in vitro screening tool for anti-fibrotic therapies using biomarkers of extracellular matrix synthesis

Prolonged Scar-in-a-Jar: an in vitro screening tool for anti-fibrotic therapies using biomarkers of extracellular matrix synthesis

Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases

Therapeutic targets in idiopathic pulmonary fibrosis

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