Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease.
Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease.
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DOI：
10.4161/onci.20297
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发表时间：
2012-08-01
期刊：
影响因子：
7.2
通讯作者：
Kuwano K
中科院分区：
文献类型：
--
作者：
Fujii S;Hara H;Araya J;Takasaka N;Kojima J;Ito S;Minagawa S;Yumino Y;Ishikawa T;Numata T;Kawaishi M;Hirano J;Odaka M;Morikawa T;Nishimura S;Nakayama K;Kuwano K
烟草烟雾诱导的加速细胞衰老与慢性阻塞性肺病（COPD）的发病机制有关。细胞衰老伴随着受损细胞成分的积累，这表明在COPD中，抑制自噬可能有助于细胞衰老。在这里，我们观察自噬是否有助于香烟烟雾提取物（CSE）诱导的原代人支气管上皮细胞（HBEC）的细胞衰老，并进一步评估COPD患者肺匀浆中p62和泛素化蛋白的水平。我们证明，CSE在HBEC中瞬间诱导自噬激活，随后加速细胞衰老，并伴随p62和泛素化蛋白的积累。自噬抑制进一步增强p62和泛素化蛋白的积累，导致衰老和衰老相关分泌表型（SASP）与白细胞介素(IL)-8分泌增加。相反，Torin1（雷帕霉素（mTOR抑制剂）的哺乳动物靶点）激活自噬，抑制p62和泛素化蛋白的积累，抑制细胞衰老。尽管基线活性增加，但COPD患者HBEC对CSE的自噬诱导显著降低。在COPD患者肺匀浆中检测到p62和泛素化蛋白的增加。受损蛋白（包括泛素化蛋白）的自噬清除不足与COPD中细胞衰老加速有关，这表明自噬在烟草烟雾诱导的衰老相关肺部疾病COPD中具有新的保护作用。
Tobacco smoke-induced accelerated cell senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cell senescence is accompanied by the accumulation of damaged cellular components suggesting that in COPD, inhibition of autophagy may contribute to cell senescence. Here we look at whether autophagy contributes to cigarette smoke extract (CSE) - induced cell senescence of primary human bronchial epithelial cells (HBEC), and further evaluate p62 and ubiquitinated protein levels in lung homogenates from COPD patients. We demonstrate that CSE transiently induces activation of autophagy in HBEC, followed by accelerated cell senescence and concomitant accumulation of p62 and ubiquitinated proteins. Autophagy inhibition further enhanced accumulations of p62 and ubiquitinated proteins, resulting in increased senescence and senescence-associated secretory phenotype (SASP) with interleukin (IL)-8 secretion. Conversely, autophagy activation by Torin1, a mammalian target of rapamycin (mTOR inhibitor), suppressed accumulations of p62 and ubiquitinated proteins and inhibits cell senescence. Despite increased baseline activity, autophagy induction in response to CSE was significantly decreased in HBEC from COPD patients. Increased accumulations of p62 and ubiquitinated proteins were detected in lung homogenates from COPD patients. Insufficient autophagic clearance of damaged proteins, including ubiquitinated proteins, is involved in accelerated cell senescence in COPD, suggesting a novel protective role for autophagy in the tobacco smoke-induced senescence-associated lung disease, COPD.
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影响因子：
3.9
作者：
Hwang, Jae-woong;Chung, Sangwoon;Sundar, Isaac K.;Yao, Hongwei;Arunachalam, Gnanapragasam;McBurney, Michael W.;Rahman, Irfan
通讯作者：
Rahman, Irfan
影响因子：
16
作者：
Kroemer G;Mariño G;Levine B
通讯作者：
Levine B
影响因子：
4.4
作者：
Lee, Hye-Mi;Shin, Dong-Min;Jo, Eun-Kyeong
通讯作者：
Jo, Eun-Kyeong
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
64.5
作者：
Kuilman, Thomas;Michaloglou, Chrysiis;Peeper, Daniel S.
通讯作者：
Peeper, Daniel S.