Background

Long-term exposure to PM_2.5 (particulate matter with an aerodynamic diameter of ≤ 2.5 μm) is associated with pulmonary injury and emphysema in patients with chronic obstructive pulmonary disease (COPD). We investigated mechanisms through which the long noncoding RNA lnc-IL7R contributes to cellular damage by inducing oxidative stress in COPD patients exposed to PM_2.5.

Methods

Associations of serum lnc-IL7R levels with lung function, emphysema, and previous PM_2.5 exposure in COPD patients were analyzed. Reactive oxygen species and lnc-IL7R levels were measured in PM_2.5-treated cells. The levels of lnc-IL7R and cellular senescence–associated genes, namely p16^INK4a and p21^CIP1/WAF1, were determined through lung tissue section staining. The effects of p16^INK4a or p21^CIP1/WAF1 regulation were examined by performing lnc-IL7R overexpression and knockdown assays. The functions of lnc-IL7R-mediated cell proliferation, cell cycle, senescence, colony formation, and apoptosis were examined in cells treated with PM_2.5. Chromatin immunoprecipitation assays were conducted to investigate the epigenetic regulation of p21^CIP1/WAF1.

Results

Lnc-IL7R levels decreased in COPD patients and were negatively correlated with emphysema or PM_2.5 exposure. Lnc-IL7R levels were upregulated in normal lung epithelial cells but not in COPD cells exposed to PM_2.5. Lower lnc-IL7R expression in PM_2.5-treated cells induced p16^INK4a and p21^CIP1/WAF1 expression by increasing oxidative stress. Higher lnc-IL7R expression protected against cellular senescence and apoptosis, whereas lower lnc-IL7R expression augmented injury in PM_2.5-treated cells. Lnc-IL7R and the enhancer of zeste homolog 2 (EZH2) synergistically suppressed p21^CIP1/WAF1 expression through epigenetic modulation.

Conclusion

Lnc-IL7R attenuates PM_2.5-mediated p21^CIP1/WAF1 expression through EZH2 recruitment, and its dysfunction may augment cellular injury in COPD.

Graphical abstract

中文翻译：

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Lnc-IL7R 通过募集 EZH2 减轻慢性阻塞性肺疾病中 PM2.5 介导的细胞衰老和细胞凋亡

背景

长期接触 PM _2.5（空气动力学直径≤ 2.5 μm 的颗粒物）与慢性阻塞性肺疾病 (COPD) 患者的肺损伤和肺气肿有关。我们研究了长链非编码 RNA lnc-IL7R 通过在暴露于 PM _2.5的 COPD 患者中诱导氧化应激而导致细胞损伤的机制。

方法

分析了 COPD 患者血清 lnc-IL7R 水平与肺功能、肺气肿和既往 PM _{2.5暴露的相关性。在 PM 2.5}处理的细胞中测量活性氧和 lnc-IL7R 水平。通过肺组织切片染色确定lnc-IL7R 和细胞衰老相关基因（即p16 ^INK4a和p21 ^{CIP1/WAF1 ）的水平。}p16 ^INK4a或p21 ^CIP1/WAF1调节的影响通过执行 lnc-IL7R 过表达和敲低测定来检查。在用 PM 处理的细胞中检查 lnc-IL7R 介导的细胞增殖、细胞周期、衰老、集落形成和细胞凋亡的功能_2.5。进行染色质免疫沉淀测定以研究p21 ^CIP1/WAF1的表观遗传调控。

结果

COPD 患者的 Lnc-IL7R 水平降低，并且与肺气肿或 PM _2.5暴露呈负相关。Lnc-IL7R 水平在正常肺上皮细胞中上调，但在暴露于 PM _2.5的 COPD 细胞中没有上调。_{PM 2.5}处理的细胞中较低的 lnc-IL7R 表达通过增加氧化应激诱导 p16 ^INK4a和 p21 ^{CIP1/WAF1表达。}较高的 lnc-IL7R 表达可防止细胞衰老和细胞凋亡，而较低的 lnc-IL7R 表达会增加 PM _2.5处理细胞的损伤。Lnc-IL7R 和 zeste 同系物 2 (EZH2) 的增强子通过表观遗传调控协同抑制p21 ^{CIP1/WAF1表达。}

结论

Lnc-IL7R 通过 EZH2 募集减弱 PM _2.5介导的p21 ^CIP1/WAF1表达，其功能障碍可能会增加 COPD 中的细胞损伤。

图形概要