Therapeutic advances in idiopathic pulmonary fibrosis

George, Gautam; Vaid, Urvashi; Summer, Ross

doi:10.1002/cpt.283

Cited by 8 publications

(7 citation statements)

References 5 publications

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“…Lung transplantation was considered the only available intervention until recently. In October of 2015, two drugs, Nintedanib and Pirfenidone, were approved by the United States Food and Drug Administration (FDA) for the treatment of IPF (George et al, 2016 ). Neither of these available therapies is curative.…”

Section: Introductionmentioning

confidence: 99%

Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis

et al. 2016

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Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited with enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGF-β1 receptor ligand signaling in fibroblasts. PGE2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. Thus, a two-hit therapeutic intervention strategy may prove necessary to halt and reverse disease dynamics.

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Section: Introductionmentioning

confidence: 99%

Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis

et al. 2016

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“…4 So far, there are only 2 drugs for IPF treatment-the recently Food and Drug Administration-approved antifibrotic agents pirfenidone and nintedanib. [5][6][7] However, other targets are urgently needed, because available treatments may decelerate disease progression, but can neither halt nor cure the disease. 7 There is strong evidence supporting the role of eicosanoids in disease models of IPF, and especially prostaglandins (PGs), with the exception of PGF 2a , seem to exert beneficial effects.…”

mentioning

confidence: 99%

“…[5][6][7] However, other targets are urgently needed, because available treatments may decelerate disease progression, but can neither halt nor cure the disease. 7 There is strong evidence supporting the role of eicosanoids in disease models of IPF, and especially prostaglandins (PGs), with the exception of PGF 2a , seem to exert beneficial effects. 8,9 Studies have shown that PGE 2 inhibits fibroblast proliferation, 10 decreases alveolar epithelial cell apoptosis, 11 is protective in bleomycin-induced pulmonary fibrosis in mice, 12,13 and inhibits myofibroblast differentiation in vitro.…”

mentioning

confidence: 99%

Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue

Bärnthaler

Theiler

Zabini

et al. 2020

Journal of Allergy and Clinical Immunology

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“…Specifically, nintedanib competitively blocks the binding sites of platelet-derived growth factor receptor, vascular endothelial growth factor receptor, and fibroblast growth factor receptor. 21 Additionally, it may have pleiotropic effects on profibrotic cytokines.…”

Section: Nintedanibmentioning

confidence: 99%

Impact of novel antifibrotic therapy on patient outcomes in idiopathic pulmonary fibrosis: patient selection and perspectives

Graney¹,

Lee²

2018

PROM

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Patients with idiopathic pulmonary fibrosis, an incurable, progressive fibrotic interstitial lung disease, suffer an impaired quality of life due to symptoms, resultant functional limitations, and the constraints of supplemental oxygen. Two antifibrotic medications, nintedanib and pirfenidone, are approved for the treatment of idiopathic pulmonary fibrosis. Both medications slow the rate of decline of lung function, but their effect on patient-reported outcomes is not yet fully understood. Nintedanib may slow the decline in health-related quality of life for treated patients. Pirfenidone may slow the progression of dyspnea and improve cough. Patients and providers should participate in shared decision-making when starting antifibrotic therapy, taking into consideration the benefits of treatment in addition to drug-related side effects and dosing schedules. Although antifibrotic therapy may have an impact on health-related quality of life, providers should also focus on comprehensive care of the patient to improve health-related outcomes. This includes a multidisciplinary evaluation, diagnosis and treatment of comorbid medical conditions, and referral to and participation in a pulmonary rehabilitation program.

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Therapeutic advances in idiopathic pulmonary fibrosis

Cited by 8 publications

References 5 publications

Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis

Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis

Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue

Impact of novel antifibrotic therapy on patient outcomes in idiopathic pulmonary fibrosis: patient selection and perspectives

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