Kato Kosuke, Papageorgiou Ioannis, Shin Yoon-Joo, Kleinhenz Jennifer M, Palumbo Sunny, Hahn Seongmin, Irish Joseph D, Rounseville Skye P, Knox Kenneth S, Hecker Louise
Division of Pulmonary, Allergy and Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
Division of Pulmonary, Allergy and Critical Care and Sleep Medicine, Department of Medicine, University of Arizona, Tucson, AZ 85721, USA.
Antioxidants (Basel). 2022 Feb 28;11(3):492. doi: 10.3390/antiox11030492.
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.
特发性肺纤维化（IPF）是一种严重且致命的肺纤维化形式，被广泛认为是一种衰老相关疾病。我们之前证明，患有持续性肺纤维化的老年小鼠和IPF肺肌成纤维细胞表现出Nrf2介导的抗氧化反应缺陷。富马酸二甲酯（Tecfidera）是一种经美国食品药品监督管理局（FDA）批准的口服药物，用于治疗多发性硬化症，其活性药物成分是富马酸二甲酯（DMF），一种活性Nrf2激活剂。然而，尚无研究评估DMF对年龄相关的持续性肺纤维化的疗效。在此，我们证明，在IPF肺成纤维细胞中，DMF治疗可抑制转化生长因子-β（TGF-β）介导的促纤维化表型，并使已确立的促纤维化表型发生逆转。我们还在博来霉素诱导的持续性肺纤维化衰老小鼠模型中评估了肺靶向（吸入）与全身（口服）给药DMF的临床前疗效。当小鼠出现无法消退的肺纤维化时，从损伤后3至6周开始，通过口服灌胃或鼻内给药，每天给老年小鼠施用DMF或赋形剂。与全身（口服）给药相比，只有肺靶向（吸入）给药的DMF恢复了肺Nrf2表达水平，降低了肺氧化应激，并促进了年龄依赖性已确立纤维化的消退。这是第一项证明肺靶向递送DMF促进年龄依赖性已确立肺纤维化消退疗效的研究。
