Unwinding the Collagen Fibrils: Elucidating the Mechanism of Pirfenidone and Nintedanib in Pulmonary Fibrosis

Bahudhanapati, Harinath; Kass, Daniel J.

doi:10.1165/rcmb.2017-0079ed

Cited by 13 publications

(12 citation statements)

References 13 publications

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“…Future studies would address the upstream signaling mechanisms that lead to both Smad2/3 and AP-1 activation. These could be tested with the FDA-approved drugs for IPF, pirfenidone and nintedanib, both of which may be associated with fibrotic signaling (32). In addition, several current clinical trials in IPF are testing cell-signaling inhibitors that may be relevant here including the c-Jun-NH 2 terminal kinase 2 (JNK2) inhibitor (33) or a PI3K/mTOR inhibitor (34).…”

Section: Mir-144-3p Targets Rxfp1 Expression In Ipfmentioning

confidence: 99%

MicroRNA-144-3p targets relaxin/insulin-like family peptide receptor 1 (RXFP1) expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis

Bahudhanapati

Tan

Dutta

et al. 2019

Journal of Biological Chemistry

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Section: Mir-144-3p Targets Rxfp1 Expression In Ipfmentioning

confidence: 99%

MicroRNA-144-3p targets relaxin/insulin-like family peptide receptor 1 (RXFP1) expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis

Bahudhanapati

Tan

Dutta

et al. 2019

Journal of Biological Chemistry

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“…The first effective disease-modifying drugs to be approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) were pirfenidone and nintedanib, which have succeeded in attenuating lung function decline in patients with IPF [17,18]. There is still no cure for IPF, thus new therapeutic options are being explored [19,20]. One group of therapies that is being tested in clinical trials is inhibitors of the mammalian target of rapamycin (mTOR).…”

Section: Introductionmentioning

confidence: 99%

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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“…PFD was originally recognized as a small-molecule p38γ inhibitor that blocks the synthesis of TGF-β [ 117 ]. However, the inhibitory effect on p38 has been excluded from the key antifibrotic mechanisms of PFD [ 118 ]. Currently, a clinical trial with the SAPK inhibitor for IPF in phase II is in progress, in which an orally active inhibitor of JNK1, CC-90001, is being studied (clinicaltrials.gov, registration number NCT03142191).…”

Section: Is An Anti-sapk Strategy Effective Against Ipf?mentioning

confidence: 99%

Pathophysiological Roles of Stress-Activated Protein Kinases in Pulmonary Fibrosis

Kasuya

Kim

Hatano

et al. 2021

IJMS

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Idiopathic pulmonary fibrosis (IPF) is one of the most symptomatic progressive fibrotic lung diseases, in which patients have an extremely poor prognosis. Therefore, understanding the precise molecular mechanisms underlying pulmonary fibrosis is necessary for the development of new therapeutic options. Stress-activated protein kinases (SAPKs), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38) are ubiquitously expressed in various types of cells and activated in response to cellular environmental stresses, including inflammatory and apoptotic stimuli. Type II alveolar epithelial cells, fibroblasts, and macrophages are known to participate in the progression of pulmonary fibrosis. SAPKs can control fibrogenesis by regulating the cellular processes and molecular functions in various types of lung cells (including cells of the epithelium, interstitial connective tissue, blood vessels, and hematopoietic and lymphoid tissue), all aspects of which remain to be elucidated. We recently reported that the stepwise elevation of intrinsic p38 signaling in the lungs is correlated with a worsening severity of bleomycin-induced fibrosis, indicating an importance of this pathway in the progression of pulmonary fibrosis. In addition, a transcriptome analysis of RNA-sequencing data from this unique model demonstrated that several lines of mechanisms are involved in the pathogenesis of pulmonary fibrosis, which provides a basis for further studies. Here, we review the accumulating evidence for the spatial and temporal roles of SAPKs in pulmonary fibrosis.

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Unwinding the Collagen Fibrils: Elucidating the Mechanism of Pirfenidone and Nintedanib in Pulmonary Fibrosis

Cited by 13 publications

References 13 publications

MicroRNA-144-3p targets relaxin/insulin-like family peptide receptor 1 (RXFP1) expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis

MicroRNA-144-3p targets relaxin/insulin-like family peptide receptor 1 (RXFP1) expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis

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

Pathophysiological Roles of Stress-Activated Protein Kinases in Pulmonary Fibrosis

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