Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis.

Kosuke Kato,Skye P Rounseville,Yoon-Joo Shin,Louise Hecker,Seongmin Hahn,Joseph D Irish,Sunny Palumbo,Kenneth S Knox,Ioannis Papageorgiou,Jennifer M Kleinhenz

doi:10.3390/antiox11030492

Kosuke Kato, Skye P Rounseville + Show 8 more

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https://doi.org/10.3390/antiox11030492

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Abstract

Idiopathic pulmonary fibrosis (IPF), a severe and deadly form of lung fibrosis, is widely regarded as a disease of aging. We previously demonstrated that aged mice with persistent lung fibrosis and IPF lung myofibroblasts exhibit deficient Nrf2-mediated antioxidant responses. Tecfidera is an orally administered FDA-approved drug for the treatment of multiple sclerosis, where the active pharmaceutical ingredient is dimethyl fumarate (DMF), an active Nrf2 activator. However, no studies have evaluated the efficacy of DMF for age-associated persistent lung fibrosis. Here, we demonstrate that in IPF lung fibroblasts, DMF treatment inhibited both TGF-β-mediated pro-fibrotic phenotypes and led to a reversal of established pro-fibrotic phenotypes. We also evaluated the pre-clinical efficacy of lung-targeted (inhaled) vs. systemic (oral) delivery of DMF in an aging murine model of bleomycin-induced persistent lung fibrosis. DMF or vehicle was administered daily to aged mice by oral gavage or intranasal delivery from 3–6 weeks post-injury when mice exhibited non-resolving lung fibrosis. In contrast to systemic (oral) delivery, only lung-targeted (inhaled) delivery of DMF restored lung Nrf2 expression levels, reduced lung oxidative stress, and promoted the resolution of age-dependent established fibrosis. This is the first study to demonstrate the efficacy of lung-targeted DMF delivery to promote the resolution of age-dependent established lung fibrosis.

Highlights

Human fibrotic disorders affect many organ systems, including the heart, blood vessels, kidneys, liver, and lungs [1,2]
In idiopathic pulmonary fibrosis (IPF) lung fibroblasts, decreased nuclear factor erythroid 2–related factor 2 (Nrf2) expression was associated with profibrogenic phenotypes [20]
Nrf2 activation restored antioxidant responses and promoted dedifferentiation of IPF myofibroblast [20]. In line with these findings, our previous studies demonstrated that IPF lung myofibroblasts exhibit defective Nrf2 responses associated with oxidative stress [19]

Summary

Introduction

Human fibrotic disorders affect many organ systems, including the heart, blood vessels, kidneys, liver, and lungs [1,2]. An estimated 45% of deaths in the U.S are attributable to disorders that are characterized by varying degrees of fibrosis [2]. The most severe form of lung fibrosis is idiopathic pulmonary fibrosis (IPF), a fatal and relentlessly progressive disorder [3,4]. IPF is characterized by excessive scar tissue formation and irreversible destruction of the lung parenchyma, resulting in gas-exchange abnormalities and respiratory failure. Two drugs have gained FDA approval for IPF (nintedanib and pirfenidone), neither are shown to definitively improve quality of life or survival. Both drugs are shown to inhibit the development of fibrosis, we recently reported that nintedanib failed to demonstrate efficacy for reversing age-associated established lung

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