The Antiretroviral Agent Nelfinavir Mesylate: A Potential Therapy for Systemic Sclerosis
| Autor: | Stephen S. MacKinnon, Joseph A. Lasky, Debasis Mondal, Taylor Fuselier, Steven Molinski, Rafael Gongora, Cecilia G. Sanchez, Meredith L. Sosulski |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Pulmonary Fibrosis Immunology Cell Culture Techniques Lung injury Transforming Growth Factor beta1 03 medical and health sciences Mice Rheumatology Fibrosis Pulmonary fibrosis Immunology and Allergy Medicine Animals Humans Computer Simulation Mechanistic target of rapamycin Lung Skin Nelfinavir Scleroderma Systemic biology business.industry Autophagy Cell Differentiation Fibroblasts medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology Anti-Retroviral Agents Cancer research biology.protein business Transforming growth factor Nelfinavir mesylate medicine.drug Signal Transduction |
| Zdroj: | Arthritisrheumatology (Hoboken, N.J.). 70(1) |
| ISSN: | 2326-5205 |
| Popis: | Objective Transforming growth factor β1 (TGFβ1) is considered a key factor in fibrogenesis, and blocking TGFβ1 signaling pathways diminishes fibrogenesis in animal models. The objective of this study was to determine whether nelfinavir mesylate (NFV), a drug approved by the Food and Drug Administration (FDA) for treating HIV infection, could be repurposed to treat pulmonary fibrosis in patients with systemic sclerosis (SSc). Methods Normal human lung, ventricular, and skin fibroblasts as well as lung fibroblasts from SSc patients were used to determine the effects of NFV on fibroblast-to-myofibroblast differentiation mediated by TGFβ1. The efficacy of NFV was also evaluated in an animal model of SSc (bleomycin-induced pulmonary fibrosis). In addition, in silico analysis was performed to determine novel off-target effects of NFV. Results NFV inhibited TGFβ1-mediated fibroblast-to-myofibroblast differentiation in lung fibroblasts through inhibition of the TGFβ1 canonical pathway. NFV also inhibited differentiation of skin and ventricular fibroblasts and adipocyte precursors into myofibroblasts. Activation of the TGFβ1/mechanistic target of rapamycin pathway inhibited autophagy in lung fibroblasts, favoring collagen deposition, and NFV counteracted this effect in a dose-dependent manner. Moreover, NFV significantly reduced lung injury and collagen deposition in an animal model of SSc. In silico analysis of NFV binding proteins revealed new putative beneficial mechanisms of action, consistent with known common pathways in fibrogenesis. Conclusion NFV abrogates TGFβ1-mediated fibroblast-to-myofibroblast differentiation and pulmonary fibrosis through off-target protein binding, a finding that supports consideration of this FDA-approved medication as an antifibrotic agent. |
| Databáze: | OpenAIRE |
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