Mitochondrial-Targeted Antioxidant Therapy Decreases Transforming Growth Factor-β-Mediated Collagen Production in a Murine Asthma Model (Publication with Expression of Concern. See vol. 63, pg. 868, 2020)
Mitochondrial-Targeted Antioxidant Therapy Decreases Transforming Growth Factor-β-Mediated Collagen Production in a Murine Asthma Model (Publication with Expression of Concern. See vol. 63, pg. 868, 2020)
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DOI：
10.1165/rcmb.2013-0519oc
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发表时间：
2015-01-01
影响因子：
6.4
通讯作者：
Anderson, Mark E.
中科院分区：
文献类型：
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作者：
Jaffer, Omar A.;Carter, A. Brent;Anderson, Mark E.
哮喘是一种急性和慢性炎症疾病，细胞因子在协调过敏性炎症反应中发挥着关键作用。 IL-13 和转化生长因子 (TGF)-β 促进纤维化气道重塑，这是导致疾病严重程度的主要原因。需要加深理解，因为目前的疗法不足以抑制气道纤维化的发展。已知 IL-13 可以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，我们测试了这样的假设：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介。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过敏原增强线粒体ROS的途径，这是TGF-β激活和增强气道成纤维细胞中胶原蛋白产生和沉积的重要上游信号。我们发现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。来自气道上皮的 TGF-β 刺激成纤维细胞中的胶原蛋白表达，有助于培养的人气道细胞和卵清蛋白攻击的小鼠对过敏原暴露的早期纤维化反应。使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)三苯基氯化膦 (mitoTEMPO) 进行治疗，可显着减弱 OVA 攻击小鼠和培养的人上皮细胞中的线粒体 ROS、TGF-β 和胶原沉积。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，而 TGF-β 活性有助于过敏性哮喘的气道重塑。线粒体靶向抗氧化剂可能是未来哮喘治疗的一种新方法。
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) triphenylphosphonium 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.