核酸传感器 STING 驱动重塑，其抑制增强慢性阻塞性肺疾病的类固醇反应性。
Nucleic acid sensor STING drives remodeling and its inhibition enhances steroid responsiveness in chronic obstructive pulmonary disease.
机构信息
Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
Department of Family and Community Medicine and Behavioural Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
出版信息
PLoS One. 2023 Jul 5;18(7):e0284061. doi: 10.1371/journal.pone.0284061. eCollection 2023.
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is progressive and irreversible chronic lung inflammatory disease. Cigarette smoke, the main cause of COPD, is often associated with double-stranded DNA release which potentially activates DNA-sensing pathways, such as STING. This study, therefore, analyzed the role of STING pathway in inducing pulmonary inflammation, steroid resistance, and remodeling in COPD.
METHODS
Primary cultured lung fibroblasts were isolated from healthy non-smoker, healthy smoker, and smoker COPD individuals. The expression of STING pathway, remodeling, and steroid resistance signatures were investigated in these fibroblasts upon LPS stimulation and treatment with dexamethasone and/or STING inhibitor, at both mRNA and protein levels using qRT-PCR, western blot, and ELISA.
RESULTS
At baseline, STING was elevated in healthy smoker fibroblasts and to a higher extent in smoker COPD fibroblasts when compared to healthy non-smoker fibroblasts. Upon using dexamethasone as monotherapy, STING activity was significantly inhibited in healthy non-smoker fibroblasts but showed resistance in COPD fibroblasts. Treating both healthy and COPD fibroblasts with STING inhibitor in combination with dexamethasone additively inhibited STING pathway in both groups. Moreover, STING stimulation triggered a significant increase in remodeling markers and a reduction in HDAC2 expression. Interestingly, treating COPD fibroblasts with the combination of STING inhibitor and dexamethasone alleviated remodeling and reversed steroid hyporesponsiveness through an upregulation of HDAC2.
CONCLUSION
These findings support that STING pathway plays an important role in COPD pathogenesis, via inducing pulmonary inflammation, steroid resistance, and remodeling. This raises the possibility of using STING inhibitor as a potential therapeutic adjuvant in combination with common steroid treatment.
背景
慢性阻塞性肺疾病（COPD）是一种进行性和不可逆转的慢性肺部炎症性疾病。香烟烟雾是 COPD 的主要病因，常伴有双链 DNA 的释放，这可能激活 DNA 感应途径，如 STING。因此，本研究分析了 STING 途径在 COPD 诱导肺部炎症、类固醇耐药和重塑中的作用。
方法
从健康不吸烟者、健康吸烟者和吸烟者 COPD 个体中分离原代培养的肺成纤维细胞。在 LPS 刺激和用地塞米松和/或 STING 抑制剂处理后，使用 qRT-PCR、western blot 和 ELISA 检测这些成纤维细胞中 STING 途径、重塑和类固醇耐药特征的表达。
结果
在基线时，健康吸烟者的成纤维细胞中 STING 升高，与健康不吸烟者的成纤维细胞相比，吸烟者 COPD 患者的成纤维细胞中 STING 升高更为明显。单独用地塞米松治疗时，健康非吸烟者的成纤维细胞中 STING 活性明显受到抑制，但 COPD 患者的成纤维细胞则表现出耐药性。用 STING 抑制剂联合地塞米松治疗两组成纤维细胞均能显著抑制 STING 途径。此外，STING 刺激可显著增加重塑标志物的表达，降低 HDAC2 的表达。有趣的是，用 STING 抑制剂联合地塞米松治疗 COPD 成纤维细胞可减轻重塑，并通过上调 HDAC2 逆转类固醇低反应性。
结论
这些发现支持 STING 途径在 COPD 发病机制中发挥重要作用，通过诱导肺部炎症、类固醇耐药和重塑。这提示我们，使用 STING 抑制剂联合常规类固醇治疗可能是一种潜在的治疗辅助手段。
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