Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease.
Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease.
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DOI：
10.1016/j.jaci.2015.01.046
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
COPDMAP
中科院分区：
文献类型：
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作者：
Wiegman CH;Michaeloudes C;Haji G;Narang P;Clarke CJ;Russell KE;Bao W;Pavlidis S;Barnes PJ;Kanerva J;Bittner A;Rao N;Murphy MP;Kirkham PA;Chung KF;Adcock IM;COPDMAP
炎症和氧化应激在慢性阻塞性肺疾病（COPD）患者中起关键作用。线粒体氧化应激可能参与了氧化应激诱导的病理过程。我们试图确定氧化应激对线粒体功能在臭氧暴露小鼠和人气道平滑肌（ASM）细胞气道炎症病理生理中的影响。小鼠暴露于臭氧中，检测肺部炎症、气道高反应性（AHR）和线粒体功能。从健康受试者、吸烟者和COPD患者的支气管活检标本中分离出人类ASM细胞。在存在和不存在线粒体靶向抗氧化剂MitoQ的情况下，测量小鼠和人ASM细胞的炎症和线粒体功能。暴露于臭氧（氧化应激的一种来源）的小鼠出现与线粒体功能障碍相关的肺部炎症和AHR，反映为线粒体膜电位下降（ΔΨm），线粒体氧化应激增加，线粒体复合体I、III和V表达减少。线粒体靶向抗氧化剂MitoQ逆转线粒体功能障碍可减少炎症和AHR。与健康对照组相比，COPD患者的ASM细胞ΔΨm、三磷酸腺苷含量、复合物表达、基础和最大呼吸水平以及呼吸储备能力均降低，而线粒体活性氧（ROS）水平升高。健康吸烟者介于健康非吸烟者和COPD患者之间。过氧化氢诱导健康受试者ASM细胞线粒体功能障碍。MitoQ和铁抑制TGF-β诱导的ASM细胞增殖和CXCL8释放。COPD患者的线粒体功能障碍与线粒体ROS水平过高有关，这有助于炎症增强和细胞过度增殖。靶向线粒体ROS是COPD患者的一种有希望的治疗方法。
Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress–induced pathology. We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β–induced ASM cell proliferation and CXCL8 release. Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD.