Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-02-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/3/492 |
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| author | Kosuke Kato Ioannis Papageorgiou Yoon-Joo Shin Jennifer M. Kleinhenz Sunny Palumbo Seongmin Hahn Joseph D. Irish Skye P. Rounseville Kenneth S. Knox Louise Hecker |
| author_facet | Kosuke Kato Ioannis Papageorgiou Yoon-Joo Shin Jennifer M. Kleinhenz Sunny Palumbo Seongmin Hahn Joseph D. Irish Skye P. Rounseville Kenneth S. Knox Louise Hecker |
| author_sort | Kosuke Kato |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T20:11:46Z |
| format | Article |
| id | doaj.art-8a5e45a3bfe24430a61b06712bea26c2 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T20:11:46Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-8a5e45a3bfe24430a61b06712bea26c22023-11-24T00:13:09ZengMDPI AGAntioxidants2076-39212022-02-0111349210.3390/antiox11030492Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung FibrosisKosuke Kato0Ioannis Papageorgiou1Yoon-Joo Shin2Jennifer M. Kleinhenz3Sunny Palumbo4Seongmin Hahn5Joseph D. Irish6Skye P. Rounseville7Kenneth S. Knox8Louise Hecker9Division of Pulmonary, Allergy and Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, USADivision of Pulmonary, Allergy and Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, USADivision of Pulmonary, Allergy and Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, USADivision of Pulmonary, Allergy and Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, USADivision of Pulmonary, Allergy and Critical Care and Sleep Medicine, Department of Medicine, University of Arizona, Tucson, AZ 85721, USADivision of Pulmonary, Allergy and Critical Care and Sleep Medicine, Department of Medicine, University of Arizona, Tucson, AZ 85721, USADivision of Pulmonary, Allergy and Critical Care and Sleep Medicine, Department of Medicine, University of Arizona, Tucson, AZ 85721, USADivision of Pulmonary, Allergy and Critical Care and Sleep Medicine, Department of Medicine, University of Arizona, Tucson, AZ 85721, USADivision of Pulmonary, Allergy and Critical Care and Sleep Medicine, Department of Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USADivision of Pulmonary, Allergy and Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, USAIdiopathic 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.https://www.mdpi.com/2076-3921/11/3/492idiopathic pulmonary fibrosisdimethyl fumarateNrf2agingantioxidantreactive oxygen species |
| spellingShingle | Kosuke Kato Ioannis Papageorgiou Yoon-Joo Shin Jennifer M. Kleinhenz Sunny Palumbo Seongmin Hahn Joseph D. Irish Skye P. Rounseville Kenneth S. Knox Louise Hecker Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis Antioxidants idiopathic pulmonary fibrosis dimethyl fumarate Nrf2 aging antioxidant reactive oxygen species |
| title | Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis |
| title_full | Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis |
| title_fullStr | Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis |
| title_full_unstemmed | Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis |
| title_short | Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis |
| title_sort | lung targeted delivery of dimethyl fumarate promotes the reversal of age dependent established lung fibrosis |
| topic | idiopathic pulmonary fibrosis dimethyl fumarate Nrf2 aging antioxidant reactive oxygen species |
| url | https://www.mdpi.com/2076-3921/11/3/492 |
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