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Title: Mitochondrial-targeted antioxidant therapy decreases transforming growth factor-β-mediated collagen production in a murine asthma model.

Authors: Jaffer, Omar A; Carter, A Brent; Sanders, Philip N; Dibbern, Megan E; Winters, Christopher J; Murthy, Shubha; Ryan, Alan J; Rokita, Adam G; Prasad, Anand M; Zabner, Joseph; Kline, Joel N; Grumbach, Isabella M; Anderson, Mark E

Published In Am J Respir Cell Mol Biol, (2015 Jan)

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.

PubMed ID: 24988374 Exiting the NIEHS site

MeSH Terms: Animals; Antioxidants/pharmacology*; Asthma/chemically induced; Asthma/drug therapy*; Asthma/genetics; Asthma/metabolism*; Asthma/pathology; Cells, Cultured; Collagen/biosynthesis*; Collagen/genetics; Disease Models, Animal; Humans; Interleukin-13/metabolism; Mice; Mice, Transgenic; Mitochondria/metabolism*; Mitochondria/pathology; Organophosphorus Compounds/pharmacology*; Piperidines/pharmacology*; Reactive Oxygen Species/metabolism; Transforming Growth Factor beta/biosynthesis*; Transforming Growth Factor beta/genetics

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