title: Mitochondrial-targeted antioxidant therapy decreases transforming growth factor-β-mediated collagen production in a murine asthma model.
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.
authors.affiliation: Departments of 1 Internal Medicine.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Jaffer
authors.forename: A Brent
authors.initials: AB
authors.lastname: Carter
authors.forename: Philip N
authors.initials: PN
authors.lastname: Sanders
authors.forename: Megan E
authors.initials: ME
authors.lastname: Dibbern
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winters
authors.forename: Shubha
authors.initials: S
authors.lastname: Murthy
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Ryan
authors.forename: Adam G
authors.initials: AG
authors.lastname: Rokita
authors.forename: Anand M
authors.initials: AM
authors.lastname: Prasad
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
authors.forename: Joel N
authors.initials: JN
authors.lastname: Kline
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Grumbach
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000975:Antioxidants; D018793:Interleukin-13; C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D003094:Collagen
keywords: airway remodeling; asthma; mitochondria; reactive oxygen species