Inhibition of MRTF activation as a clinically achievable anti-fibrotic mechanism for pirfenidone

Ma, Hsiao-Yen; Heiden, Jason A. Vander; Uttarwar, Salil; Xi, Ying; N’Diaye, Elsa-Noah; LaCanna, Ryan; Caplazi, Patrick; Gierke, Sarah; Moffat, John G.; Wolters, Paul J.; Ding, Ning

doi:10.1183/13993003.00604-2022

Cited by 10 publications

(5 citation statements)

References 65 publications

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“…targeting of pro-fibrotic growth factors and transcription factors, inhibiting collagen fibril formation, and antagonizing oxidative stress [5]. It was recently demonstrated to inhibit the activation of myocardin-related transcription factor in primary human lung fibroblasts by preventing its interaction with actin [6]. In IPF, pirfenidone reduces by half the decline in lung function and further reduces overall mortality [7][8][9].…”

Section: Pirfenidone and Nintedanib In Idiopathic Pulmonary Fibrosismentioning

confidence: 99%

Evidence from recent clinical trials in fibrotic interstitial lung diseases

Cottin,

Valenzuela

2024

Current Opinion in Pulmonary Medicine

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Purpose of review Idiopathic pulmonary fibrosis (IPF) is the prototype of fibrosing interstitial lung diseases. It is mirrored by progressive pulmonary fibrosis (PPF), an umbrella term which characterizes disease behavior of various fibrotic interstitial lung diseases with irreversible progression, accounting for loss of lung function, exercise intolerance and respiratory failure leading to early mortality. Pirfenidone and nintedanib halve the decline in lung function but do not halt disease progression. Recent findings Since the publication in 2014 of pivotal pirfenidone and nintedanib studies, a number of clinical trials were conducted, many of them did not reach their primary endpoints. In IPF, promising phase 2 trials were followed by large phase 3 trials that did not confirm a favorable efficacy to tolerability favorable profile, including those with ziritaxestat, an autotaxin-1 inhibitor, zinpentraxin-alpha (human recombinant pentraxin-2), and the monoclonal antibody pamrevlumab targeting connective tissue growth factor. Nevertheless, newer compounds that hold promise are currently being evaluated in phase 3 or phase 2b randomized controlled trials, including: nerandomilast, a preferential phosphodiesterase 4B inhibitor; admilparant, a lysophosphatidic acid receptor antagonist; inhaled treprostinil, a prostacyclin agonist; and bexotegrast, a dual-selective inhibitor of αvβ6 and αvβ1 integrins. Nerandomilast, admilparant, inhaled treprostinil, and inhaled AP01 (pirfenidone), are currently studied in patients with PPF. Summary Despite recent frustrating negative results, there is a growing portfolio of candidate drugs developed in both IPF and PPF.

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Section: Pirfenidone and Nintedanib In Idiopathic Pulmonary Fibrosismentioning

confidence: 99%

Evidence from recent clinical trials in fibrotic interstitial lung diseases

Cottin,

Valenzuela

2024

Current Opinion in Pulmonary Medicine

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“…The sequencing samples were obtained from the patients' lung tissue, and the clinical features of GSE32537 include percent predicted forced vital capacity (FVC% predicted), percent predicted diffusion capacity of the lung for carbon monoxide (DLCO% predicted), and the St. George's Respiratory Questionnaire (SGRQ) scores. Additionally, 19 additional datasets (GSE27957 [28], GSE93606 [29], GSE38958 [30], GSE47460 [31], GSE135893 [32], GSE132771 [33], GSE201698, GSE129605 [34], GSE119007 [35], GSE103488 [36], GSE135097 [37], GSE226249 [38], GSE44723 [39], GSE172121 [40], GSE161322 [41], GSE97829 [42], GSE102674 [43], GSE130983 [44], GSE97826 [42]) were used for external validation of the analysis results.…”

Section: The Analysis Of Publicly Available Gene Expression Data and ...mentioning

confidence: 99%

Investigation of a UPR-Related Gene Signature Identifies the Pro-Fibrotic Effects of Thrombospondin-1 by Activating CD47/ROS/Endoplasmic Reticulum Stress Pathway in Lung Fibroblasts

Zhan,

Wei,

Liu

et al. 2023

Antioxidants

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Unfolded protein response (UPR) signaling and endoplasmic reticulum (ER) stress have been linked to pulmonary fibrosis. However, the relationship between UPR status and pulmonary function and prognosis in idiopathic pulmonary fibrosis (IPF) patients remains largely unknown. Through a series of bioinformatics analyses, we established a correlation between UPR status and pulmonary function in IPF patients. Furthermore, thrombospondin-1 (TSP-1) was identified as a potential biomarker for prognostic evaluation in IPF patients. By utilizing both bulk RNA profiling and single-cell RNA sequencing data, we demonstrated the upregulation of TSP-1 in lung fibroblasts during pulmonary fibrosis. Gene set enrichment analysis (GSEA) results indicated a positive association between TSP-1 expression and gene sets related to the reactive oxygen species (ROS) pathway in lung fibroblasts. TSP-1 overexpression alone induced mild ER stress and pulmonary fibrosis, and it even exacerbated bleomycin-induced ER stress and pulmonary fibrosis. Mechanistically, TSP-1 promoted ER stress and fibroblast activation through CD47-dependent ROS production. Treatment with either TSP-1 inhibitor or CD47 inhibitor significantly attenuated BLM-induced ER stress and pulmonary fibrosis. Collectively, these findings suggest that the elevation of TSP-1 during pulmonary fibrosis is not merely a biomarker but likely plays a pathogenic role in the fibrotic changes in the lung.

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“…Nintedanib acts by inhibiting the tyrosine kinase pathway, decreasing the proliferation, migration, and survival of lung fibroblasts and myofibroblasts, and reducing extracellular matrix deposition [ 18 , 19 ]. Pirfenidone’s activity is poorly understood, but it seems that one of its mechanisms of action is the inhibition of myocardin-related transcription factor (MRTF) activation, decreasing the cells’ mechanical stress, which might contribute to its therapeutic effect [ 19 , 20 , 21 ]. The use of Nintedanib and Pirfenidone has significant limitations, only slowing disease progress and showing little efficacy for patients in more advanced stages [ 16 , 17 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…Pirfenidone’s activity is poorly understood, but it seems that one of its mechanisms of action is the inhibition of myocardin-related transcription factor (MRTF) activation, decreasing the cells’ mechanical stress, which might contribute to its therapeutic effect [ 19 , 20 , 21 ]. The use of Nintedanib and Pirfenidone has significant limitations, only slowing disease progress and showing little efficacy for patients in more advanced stages [ 16 , 17 , 21 ]. Furthermore, they are high-cost drugs and cause side effects that often lead patients to discontinue use [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Innovative Pre-Clinical Data Using Peptides to Intervene in the Evolution of Pulmonary Fibrosis

Simon

Coelho

Junior

et al. 2023

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a progressive, relentless, and deadly disease. Little is known about its pathogenetic mechanisms; therefore, developing efficient pharmacological therapies is challenging. This work aimed to apply a therapeutic alternative using immunomodulatory peptides in a chronic pulmonary fibrosis murine model. BALB/c mice were intratracheally instilled with bleomycin (BLM) and followed for 30 days. The mice were treated with the immune modulatory peptides ToAP3 and ToAP4 every three days, starting on the 5th day post-BLM instillation. ELISA, qPCR, morphology, and respiratory function analyses were performed. The treatment with both peptides delayed the inflammatory process observed in the non-treated group, which showed a fibrotic process with alterations in the production of collagen I, III, and IV that were associated with significant alterations in their ventilatory mechanics. The ToAP3 and ToAP4 treatments, by lung gene modulation patterns, indicated that distinct mechanisms determine the action of peptides. Both peptides controlled the experimental IPF, maintaining the tissue characteristics and standard function properties and regulating fibrotic-associated cytokine production. Data obtained in this work show that the immune response regulation by ToAP3 and ToAP4 can control the alterations that cause the fibrotic process after BLM instillation, making both peptides potential therapeutic alternatives and/or adjuvants for IPF.

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Inhibition of MRTF activation as a clinically achievable anti-fibrotic mechanism for pirfenidone

Cited by 10 publications

References 65 publications

Evidence from recent clinical trials in fibrotic interstitial lung diseases

Evidence from recent clinical trials in fibrotic interstitial lung diseases

Investigation of a UPR-Related Gene Signature Identifies the Pro-Fibrotic Effects of Thrombospondin-1 by Activating CD47/ROS/Endoplasmic Reticulum Stress Pathway in Lung Fibroblasts

Innovative Pre-Clinical Data Using Peptides to Intervene in the Evolution of Pulmonary Fibrosis

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