Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis.
Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis.
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DOI：
10.3390/antiox11030492
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发表时间：
2022-02-28
期刊：
影响因子：
--
通讯作者：
Hecker L
中科院分区：
文献类型：
--
作者：
Kato K;Papageorgiou I;Shin YJ;Kleinhenz JM;Palumbo S;Hahn S;Irish JD;Rounseville SP;Knox KS;Hecker L
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疾病。我们之前证明，患有持续性肺纤维化和 IPF 肺肌成纤维细胞的老年小鼠表现出 Nrf2 介导的抗氧化反应不足。 Tecfidera 是 FDA 批准的一种口服药物，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 对与年龄相关的持续性肺纤维化的疗效。在这里，我们证明，在 IPF 肺成纤维细胞中，DMF 治疗抑制了 TGF-β 介导的促纤维化表型，并导致已建立的促纤维化表型的逆转。我们还在博来霉素诱导的持续性肺纤维化的衰老小鼠模型中评估了肺靶向（吸入）与全身（口服）递送 DMF 的临床前疗效。受伤后 3-6 周，当小鼠表现出未消退的肺纤维化时，每天通过口服强饲法或鼻内给药方式向老年小鼠施用 DMF 或载体。与全身（口服）递送相比，只有肺靶向（吸入）DMF 递送才能恢复肺 Nrf2 表达水平，减少肺氧化应激，并促进年龄依赖性纤维化的消退。这是第一项证明肺部靶向 DMF 递送对于促进年龄依赖性肺纤维化消退的功效的研究。
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.
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DOI：
10.1146/annurev-pathol-020712-163930
发表时间：
2013-01-24
期刊：
Annual review of pathology
影响因子：
--
作者：
Duffield JS;Lupher M;Thannickal VJ;Wynn TA
通讯作者：
Wynn TA
影响因子：
24.3
作者：
Beeh, KM;Beier, J;Buhl, R
通讯作者：
Buhl, R
影响因子：
24.3
作者：
Lenz, AG;Costabel, U;Maier, KL
通讯作者：
Maier, KL
影响因子：
2.3
作者：
Gagliano, Nicoletta;Grizzi, Fabio;Annoni, Giorgio
通讯作者：
Annoni, Giorgio
影响因子：
7.3
作者：
Merkt W;Bueno M;Mora AL;Lagares D
通讯作者：
Lagares D