Department of Respiratory Medicine (Department of Respiratory and Critical Care Medicine), Key Site of the National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China.
Department of Respiratory Medicine, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, Guilin, Guangxi, China.
Exp Cell Res. 2019 Nov 1;384(1):111545. doi: 10.1016/j.yexcr.2019.111545. Epub 2019 Aug 27.
Cigarette smoke (CS) is the primary risk factor for chronic obstructive pulmonary disease (COPD) and dampens antiviral response, which increases viral infections and leads to COPD acute exacerbation (AECOPD). Adenovirus, a nonenveloped DNA virus, is linked with AECOPD, whose DNAs trigger innate immune response via interacting with pattern recognition receptors (PRRs). Stimulator of interferon genes (STING), as a cytosolic DNA sensor, participates in adenovirus-induced interferon β (IFNβ)-dependent antiviral response. STING is involved in various pulmonary diseases, but role of STING in pathogenesis of AECOPD is not well documented. In the present study, we explored relationship between STING and AECOPD induced by recombinant adenovirus vectors (rAdVs) and CS in wild type (WT) and STING-/- mice; and also characterized the inhibition of STING- IFNβ pathway in pulmonary epithelium exposed to cigarette smoke extract (CSE). We found that CS or CSE exposure alone dramatically inhibited STING expression, but not significantly effected IFNβ production. Moreover, CS or CSE-exposed significantly suppressed activation of STING-IFNβ pathway induced by rAdVs and suppressed clearance of rAdVs DNA. Inflammation, fibrosis and emphysema of lung tissues were exaggerated when treated with CS plus rAdVs, which further deteriorate in absences of STING. In A549 cells with knockdown of STING, we also observed enhancing apoptosis related to emphysema, especially CSE and adenovirus vectors in combination. Therefore, STING may play a protective role in preventing the progress of COPD.
香烟烟雾（CS）是慢性阻塞性肺疾病（COPD）的主要危险因素，并抑制抗病毒反应，从而增加病毒感染并导致 COPD 急性加重（AECOPD）。腺病毒是一种无包膜的 DNA 病毒，与 AECOPD 有关，其 DNA 通过与模式识别受体（PRRs）相互作用触发先天免疫反应。干扰素基因刺激物（STING）作为一种胞质 DNA 传感器，参与腺病毒诱导的干扰素β（IFNβ）依赖性抗病毒反应。STING 参与多种肺部疾病，但 STING 在 AECOPD 发病机制中的作用尚未得到充分证实。在本研究中，我们探索了 STING 与重组腺病毒载体（rAdVs）和 CS 在野生型（WT）和 STING-/-小鼠中诱导的 AECOPD 之间的关系；并描述了暴露于香烟烟雾提取物（CSE）的肺上皮细胞中 STING-IFNβ通路的抑制作用。我们发现，CS 或 CSE 单独暴露会显著抑制 STING 表达，但对 IFNβ 产生没有明显影响。此外，CS 或 CSE 暴露显著抑制 rAdVs 诱导的 STING-IFNβ通路的激活，并抑制 rAdVs DNA 的清除。用 CS 加 rAdVs 治疗时，肺组织的炎症、纤维化和肺气肿明显加重，而 STING 缺失时则进一步恶化。在 STING 敲低的 A549 细胞中，我们还观察到与肺气肿相关的凋亡增强，尤其是 CSE 和腺病毒载体联合作用时。因此，STING 可能在预防 COPD 进展中发挥保护作用。
