| First Author | Jaffer OA | Year | 2015 |
| Journal | Am J Respir Cell Mol Biol | Volume | 52 |
| Issue | 1 | Pages | 106-15 |
| PubMed ID | 24988374 | Mgi Jnum | J:232221 |
| Mgi Id | MGI:5776330 | Doi | 10.1165/rcmb.2013-0519OC |
| Citation | Jaffer OA, et al. (2015) Mitochondrial-targeted antioxidant therapy decreases transforming growth factor-beta-mediated collagen production in a murine asthma model. Am J Respir Cell Mol Biol 52(1):106-15 |
| abstractText | 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)-beta 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-beta, 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-beta-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-beta 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-beta expression and activity. TGF-beta 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)triphenylphosphoniu m chloride (mitoTEMPO), significantly attenuated mitochondrial ROS, TGF-beta, 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-beta activity that contributes to airway remodeling in allergic asthma. Mitochondrial-targeted antioxidants may be a novel approach for future asthma therapies. |
