Mitochondrial-Targeted Antioxidant Therapy Decreases Transforming Growth Factor-β–Mediated Collagen Production in a Murine Asthma Model
Authors: Joseph Zabner
Megan E Dibbern
Shubha Murthy
Mark E Anderson
Christopher J Winters
Anand M Prasad
A Brent Carter
Isabella M Grumbach
Adam G Rokita
Alan J Ryan
Omar A Jaffer
Philip N Sanders
Joel N Kline
Journal: American Journal of Respiratory Cell and Molecular Biology (2015)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: airway remodeling; asthma; mitochondria; reactive oxygen species.
Affiliations: Departments of 1 Internal Medicine.

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. 

Retracted: No

PubPeer comments:
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 This article is currently undergoing investigation. ,