Journal article
Mitochondrial-targeted antioxidant therapy decreases transforming growth factor-β-mediated collagen production in a murine asthma model
American journal of respiratory cell and molecular biology, Vol.52(1), pp.106-115
01/2015
DOI: 10.1165/rcmb.2013-0519OC
PMCID: PMC4370251
PMID: 24988374
Abstract
Asthma is a disease of acute and chronic inflammation in which cytokines play a critical role in orchestrating the allergic inflammatory response. IL-13 and transforming growth factor (TGF)-β promote fibrotic airway remodeling, a major contributor to disease severity. Improved understanding is needed, because current therapies are inadequate for suppressing development of airway fibrosis. IL-13 is known to stimulate respiratory epithelial cells to produce TGF-β, but the mechanism through which this occurs is unknown. Here, we tested the hypothesis that reactive oxygen species (ROS) are a critical signaling intermediary between IL-13 or allergen stimulation and TGF-β-dependent airway remodeling. We used cultured human bronchial epithelial cells and an in vivo mouse model of allergic asthma to map a pathway where allergens enhanced mitochondrial ROS, which is an essential upstream signal for TGF-β activation and enhanced collagen production and deposition in airway fibroblasts. We show that mitochondria in airway epithelium are an essential source of ROS that activate TGF-β expression and activity. TGF-β from airway epithelium stimulates collagen expression in fibroblasts, contributing to an early fibrotic response to allergen exposure in cultured human airway cells and in ovalbumin-challenged mice. Treatment with the mitochondrial-targeted antioxidant, (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), significantly attenuated mitochondrial ROS, TGF-β, and collagen deposition in OVA-challenged mice and in cultured human epithelial cells. Our findings suggest that mitochondria are a critical source of ROS for promoting TGF-β activity that contributes to airway remodeling in allergic asthma. Mitochondrial-targeted antioxidants may be a novel approach for future asthma therapies.
Details
- Title: Subtitle
- Mitochondrial-targeted antioxidant therapy decreases transforming growth factor-β-mediated collagen production in a murine asthma model
- Creators
- Omar A Jaffer - Departments of 1 Internal MedicineA Brent Carter - University of Iowa, Radiation OncologyPhilip N SandersMegan E DibbernChristopher J WintersShubha Murthy - University of Iowa, Internal MedicineAlan J Ryan - University of Iowa, Internal MedicineAdam G RokitaAnand M PrasadJoseph Zabner - University of Iowa, Internal MedicineJoel N Kline - University of Iowa, Internal MedicineIsabella M Grumbach - University of Iowa, Internal MedicineMark E Anderson
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory cell and molecular biology, Vol.52(1), pp.106-115
- DOI
- 10.1165/rcmb.2013-0519OC
- PMID
- 24988374
- PMCID
- PMC4370251
- NLM abbreviation
- Am J Respir Cell Mol Biol
- ISSN
- 1044-1549
- eISSN
- 1535-4989
- Grant note
- I01 BX001135 / BLRD VA P30 ES005605 / NIEHS NIH HHS 2R01ES015981-06 / NIEHS NIH HHS T32 HL007121 / NHLBI NIH HHS R01 ES015981 / NIEHS NIH HHS
- Language
- English
- Date published
- 01/2015
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Occupational and Environmental Health; Anatomy and Cell Biology; Cardiovascular Medicine; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984088507702771
Metrics
20 Record Views