1. Mitochondrial-targeted antioxidant therapy decreases transforming growth factor-β-mediated collagen production in a murine asthma model.
- Author
-
Jaffer OA, Carter AB, Sanders PN, Dibbern ME, Winters CJ, Murthy S, Ryan AJ, Rokita AG, Prasad AM, Zabner J, Kline JN, Grumbach IM, and Anderson ME
- Subjects
- Animals, Asthma chemically induced, Asthma genetics, Asthma pathology, Cells, Cultured, Collagen genetics, Disease Models, Animal, Humans, Interleukin-13 metabolism, Mice, Mice, Transgenic, Mitochondria pathology, Reactive Oxygen Species metabolism, Transforming Growth Factor beta genetics, Antioxidants pharmacology, Asthma drug therapy, Asthma metabolism, Collagen biosynthesis, Mitochondria metabolism, Organophosphorus Compounds pharmacology, Piperidines pharmacology, Transforming Growth Factor beta biosynthesis
- 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.
- Published
- 2015
- Full Text
- View/download PDF