DNA damage as a molecular link in the pathogenesis of COPD in smokers
DNA damage as a molecular link in the pathogenesis of COPD in smokers
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DOI：
10.1183/09031936.00050211
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发表时间：
2012-06-01
影响因子：
24.3
通讯作者：
Nagai, Atsushi
中科院分区：
文献类型：
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作者：
Aoshiba, Kazutetsu;Zhou, Fang;Nagai, Atsushi
为了探讨DNA双链断裂（DSB）在慢性阻塞性肺疾病（COPD）发病中的作用，我们对COPD患者、无症状吸烟者和非吸烟者的肺组织标本进行了DSB标记物的免疫荧光染色，结果发现DSB灶的数目与COPD的发病有关。（磷酸化组蛋白2AX（γ H2 AX），磷酸化ATM（共济失调毛细血管扩张突变）底物和磷酸化p53结合蛋白-1灶）COPD患者肺泡I、II型细胞和内皮细胞的平均每细胞数高于无症状吸烟者和非吸烟者。在肺组织中，II型细胞中每个细胞含有更多的γ H2 AX病灶，表达p16（INK 4a）（p16）、磷酸化核因子（NF）-κ B和白细胞介素（IL）-6的II型细胞以及表达活性半胱天冬酶-3的肺泡壁细胞的百分比更高。每个细胞中含有较高数量γ H2 AX灶的II型细胞具有较高的p16、磷酸化NF-κ B和IL-6表达率。表达活性半胱天冬酶-3的肺泡壁细胞中有一半含有γ H2 AX病灶。8-羟基-2-脱氧鸟苷染色阳性的II型细胞比染色阴性的II型细胞含有更多的γ H2 AX病灶。总之，DSB，至少部分由氧化应激引起，似乎有助于COPD的发病机制，诱导细胞凋亡，细胞衰老和促炎反应。
In this study, we investigated whether DNA double-strand breaks (DSBs) contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD).We immunofluorescence-stained lung tissue samples obtained from COPD patients, asymptomatic smokers and nonsmokers for markers of DSBs.The numbers of DSB foci (phosphorylated histone 2AX (gamma H2AX), phosphorylated ATM (ataxia telangiectasia mutated) substrate and phosphorylated p53-binding protein-1 foci) per cell in alveolar type I and II cells and endothelial cells were higher in the COPD patients than in the asymptomatic smokers and nonsmokers. The lung tissue in which type II cells contained higher numbers of gamma H2AX foci per cell had higher percentages of type II cells that expressed p16(INK4a) (p16), phosphorylated nuclear factor (NF)-kappa B and interleukin (IL)-6, and of alveolar wall cells that expressed active caspase-3. The type II cells that contained higher numbers of gamma H2AX foci per cell had higher rates of expression of p16, phosphorylated NF-kappa B, and IL-6. Half of the alveolar wall cells that expressed active-caspase-3 contained gamma H2AX foci. Type ll cells that stained positive for 8-hydroxy-2-deoxyguanosine contained a higher number of gamma H2AX foci per cell than the type II cells that stained negative.In conclusion, DSBs, at least in part caused by oxidative stress, appear to contribute to the pathogenesis of COPD by inducing apoptosis, cell senescence and pro-inflammatory responses.