Mitochondrial fragmentation in cigarette smoke induced-bronchial epithelial-猫眼课题宝

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2013

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Hiromichi Hara;J. Araya;Saburo Ito;Kenji Kobayashi;Yutaka Yoshii;H. Wakui;Jun Kojima;Kenichiro Shimizu;T. Numata;M. Kawaishi;N. Kamiya;M. Odaka;T. Morikawa;Yumi;K. Nakayama;K. Kuwano

理论基础：线粒体是动态细胞器，通过分裂和融合不断改变其形状。线粒体动力学的破坏与疾病病理有关，原因是产生了过量的活性氧(ROS)。23香烟烟雾(CS)暴露引起的细胞衰老加速24 ROS产生过多与慢性阻塞性肺疾病(COPD)的发病机制有关。因此，我们研究了26个线粒体动力学和ROS的产生在CS提取物(CSE)诱导的人支气管上皮细胞(HBEC)27细胞衰老中的作用。方法：用电子显微镜和29荧光显微镜观察线粒体形态。采用衰老相关β-半乳糖苷酶(SA-β-GAL)30染色和p21蛋白免疫印迹法检测31例细胞的衰老情况。线粒体特异性超氧化物歧化产物测定采用MitoSOX染色。通过siRNA转染法敲除33个线粒体融合蛋白(OPA1或Mitofusins)，诱导线粒体碎裂。34-乙酰半胱氨酸(NAC)和Mito-Tempo作为抗氧化剂。结果：COPD肺组织线粒体细胞更易碎片化。CSE诱导的线粒体断裂和线粒体ROS的产生是导致HBEC加速的原因之一。通过敲除融合蛋白诱导的线粒体断裂也增加了线粒体ROS的产生和40%的衰老细胞。在42种抗氧化剂存在下，CSE处理后HBEC的衰老和线粒体41的断裂被抑制。43结论：CSE诱导的线粒体断裂通过线粒体ROS的产生机制参与了细胞44的衰老。因此，线粒体动力学紊乱可能是46例慢性阻塞性肺疾病发病序列的一部分。47例非COPD吸烟者和COPD患者吸烟者。在肺组织的电子显微镜检查中，我们发现COPD患者的支气管上皮细胞线粒体有碎裂的趋势，而非COPD吸烟者则无此现象，提示线粒体动力学在COPD发病机制中占主导地位。这些结果与以前的报道一致，表明COPD患者骨骼肌中的线粒体往往较小，并伴随着ROS产生的增加(16，37，39)。

: 20 Rationale : Mitochondria are dynamic organelles, which continuously change their 21 shape through fission and fusion. Disruption of mitochondrial dynamics is involved 22 in disease pathology through excessive reactive oxygen species (ROS) production. 23 Accelerated cellular senescence resulting from cigarette smoke (CS) exposure 24 with excessive ROS production has been implicated in the pathogenesis of chronic 25 obstructive pulmonary disease (COPD). Hence, we investigated the involvement of 26 mitochondrial dynamics and ROS production in terms of CS extract (CSE)-induced 27 cellular senescence in human bronchial epithelial cells (HBEC). 28 Methods : Mitochondrial morphology was examined by electron microscopy and 29 fluorescence microscopy. Senescence associated beta-galactosidase (SA- β -gal) 30 staining and p21 western blotting of primary HBEC were performed to evaluate 31 cellular senescence. Mitochondrial specific superoxide production was measured 32 by MitoSOX staining. Mitochondrial fragmentation was induced by knockdown of 33 mitochondrial fusion proteins (OPA1 or Mitofusins) by siRNA transfection. 34 N-acetylcysteine (NAC), and Mito-TEMPO were used as antioxidants. Results : Mitochondria cells were prone to be more fragmented in COPD lung tissues. CSE induced mitochondrial fragmentation and mitochondrial ROS production, which were responsible for acceleration of HBEC. Mitochondrial fragmentation induced 39 by knockdown of fusion proteins also increased mitochondrial ROS production and 40 percentages of senescent cells. HBEC senescence and mitochondria 41 fragmentation in response to CSE treatment were inhibited in the presence of 42 antioxidants. 43 Conclusions: CSE-induced mitochondrial fragmentation is involved in cellular 44 senescence through the mechanism of mitochondrial ROS production. Hence, 45 disruption of mitochondrial dynamics may be a part of the pathogenic sequence of 46 COPD development. 47 smokers without COPD and from COPD patients. In electron microscopic examination of lung tissues, we demonstrated that mitochondria in bronchial epithelial cells tended to be fragmented in COPD but not in smokers without COPD, suggesting the fission process dominancy of mitochondrial dynamics in COPD pathogenesis. These results are in accordance with previous reports demonstrating that mitochondria in skeletal muscles from COPD patients tended to be smaller in size accompanied by increased ROS production(16, 37, 39).

Mitochondrial fragmentation in cigarette smoke induced-bronchial epithelial

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