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
Departments of 1 Internal Medicine.
Am J Respir Cell Mol Biol. 2015 Jan;52(1):106-15. doi: 10.1165/rcmb.2013-0519OC.
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.
哮喘是一种急慢性炎症性疾病，细胞因子在协调过敏性炎症反应中起关键作用。白细胞介素-13（IL-13）和转化生长因子（TGF）-β促进气道纤维化重塑，这是导致疾病严重程度的主要因素。由于目前的治疗方法不足以抑制气道纤维化的发展，因此需要更好地了解其机制。已知IL-13可刺激呼吸道上皮细胞产生TGF-β，但其发生机制尚不清楚。在这里，我们测试了以下假设：活性氧（ROS）是IL-13或过敏原刺激与TGF-β依赖性气道重塑之间的关键信号中间体。我们使用培养的人支气管上皮细胞和过敏性哮喘的体内小鼠模型来绘制一条途径，其中过敏原增强了线粒体ROS，这是TGF-β激活以及气道成纤维细胞中胶原蛋白产生和沉积增加的重要上游信号。我们表明气道上皮中的线粒体是激活TGF-β表达和活性的ROS的重要来源。气道上皮中的TGF-β刺激成纤维细胞中的胶原蛋白表达，有助于在培养的人气道细胞和卵清蛋白激发的小鼠中对过敏原暴露产生早期纤维化反应。用线粒体靶向抗氧化剂（2-(2,2,6,6-四甲基哌啶-1-氧基-4-基氨基)-2-氧代乙基）三苯基氯化鏻（mitoTEMPO）处理可显著减弱卵清蛋白激发小鼠和培养的人上皮细胞中的线粒体ROS、TGF-β和胶原蛋白沉积。我们的研究结果表明线粒体是促进TGF-β活性的ROS的关键来源，TGF-β活性有助于过敏性哮喘中的气道重塑。线粒体靶向抗氧化剂可能是未来哮喘治疗的一种新方法。
