Zhao Peng, Liu Xuefang, Dong Haoran, Tian Yange, Feng Suxiang, Zhao Di, Ren Zhouxin, Zhang Lanxi, Li Jiansheng
Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, China.
Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, China.
Front Pharmacol. 2020 Aug 7;11:1212. doi: 10.3389/fphar.2020.01212. eCollection 2020.
Bufei Yishen formula (BYF) is a Traditional Chinese Medicine (TCM) reported to ameliorate chronic obstructive pulmonary disease (COPD) by regulating the balance between T helper (Th) 17 and regulatory T (Treg) cells. However, its mechanism remains unknown. Therefore, this study aimed to explore the underlying mechanisms of BYF. Naïve CD4+ T cells were exposed to anti-CD3, anti-CD28, transforming growth factor (TGF)-β, and/or interleukin (IL)-6 to promote their differentiation into Th17 or Treg cells. A rat model of cigarette smoke- and bacterial infection-induced COPD was established and orally treated with BYF and/or an adenosine 2a receptor (A2aR) antagonist. Then, the rats were sacrificed, their lung tissues were removed for histological analysis, and their spleens were collected to evaluate Th17 and Treg cells. The results showed that BYF significantly suppressed Th17 cell differentiation and its related cytokines and enhanced Treg cell differentiation and its related cytokines. In addition, BYF activated the A2aR, increased the levels of p-signal transducer and activator of transcription (STAT)5, and decreased the level of p-STAT3 in Treg and Th17 cells. The A2aR antagonist suppressed the changes induced by BYF treatment in Th17 and Treg cells. Furthermore, the A2aR antagonist diminished the therapeutic effect of BYF on COPD, as indicated by the lung injury scores, bronchiole wall thickness, small pulmonary vessels wall thickness, bronchiole stenosis, alveolar diameters, decrease in inflammatory cytokines, increase in alveolar number, and lung functions. Similarly, the A2aR antagonist reversed the effects of BYF on the proportion of Th17 and Treg cells in the spleen. Additionally, BYF increased the protein and mRNA levels of A2aR and regulated the phosphorylation of STAT3 and STAT5 in spleen and lung tissues, which were inhibited by cotreatment with the A2aR antagonist. In conclusion, this study suggested that BYF exhibited its anti-COPD efficacy by restoring the Th17/Treg balance activating A2aR, which may provide evidence for the clinical application of BYF in the treatment of COPD.
补肺益肾方（BYF）是一种据报道可通过调节辅助性T细胞（Th）17和调节性T细胞（Treg）之间的平衡来改善慢性阻塞性肺疾病（COPD）的中药。然而，其机制尚不清楚。因此，本研究旨在探讨补肺益肾方的潜在机制。将未活化的CD4+ T细胞暴露于抗CD3、抗CD28、转化生长因子（TGF）-β和/或白细胞介素（IL）-6中，以促进其分化为Th17或Treg细胞。建立香烟烟雾和细菌感染诱导的COPD大鼠模型，并口服补肺益肾方和/或腺苷2a受体（A2aR）拮抗剂进行治疗。然后，处死大鼠，取出肺组织进行组织学分析，并收集脾脏以评估Th17和Treg细胞。结果表明，补肺益肾方显著抑制Th17细胞分化及其相关细胞因子，并增强Treg细胞分化及其相关细胞因子。此外，补肺益肾方激活A2aR，增加Treg和Th17细胞中磷酸化信号转导和转录激活因子（STAT）5的水平，并降低磷酸化STAT3的水平。A2aR拮抗剂抑制了补肺益肾方治疗诱导的Th17和Treg细胞变化。此外，A2aR拮抗剂削弱了补肺益肾方对COPD的治疗效果，这通过肺损伤评分、细支气管壁厚度、小肺血管壁厚度、细支气管狭窄、肺泡直径、炎症细胞因子减少、肺泡数量增加和肺功能得以体现。同样，A2aR拮抗剂逆转了补肺益肾方对脾脏中Th17和Treg细胞比例的影响。此外，补肺益肾方增加了A2aR的蛋白质和mRNA水平，并调节了脾脏和肺组织中STAT3和STAT5的磷酸化，而A2aR拮抗剂共同处理可抑制这些作用。总之，本研究表明补肺益肾方通过恢复Th17/Treg平衡和激活A2aR发挥其抗COPD疗效，这可能为补肺益肾方在COPD治疗中的临床应用提供依据。
