Restoring Th17/Treg balance via modulation of STAT3 and STAT5 activation contributes to the amelioration of chronic obstructive pulmonary disease by Bufei Yishen formula
Restoring Th17/Treg balance via modulation of STAT3 and STAT5 activation contributes to the amelioration of chronic obstructive pulmonary disease by Bufei Yishen formula
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补肺益肾方通过调节STAT3和STAT5激活恢复Th17/Treg平衡有助于改善慢性阻塞性肺疾病
DOI：
10.1016/j.jep.2018.02.023
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发表时间：
2018-05-10
影响因子：
5.4
通讯作者：
Zhang, Lanxi
中科院分区：
文献类型：
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作者：
Zhao, Peng;Li, Jiansheng;Zhang, Lanxi
民族药理学相关性：补肺益肾方（BYF）作为一种中药，已广泛应用于慢性阻塞性肺疾病（COPD）的临床治疗，为COPD患者肺肾气虚证提供了有效的治疗策略。在此，我们研究了其在COPD大鼠中的抗COPD机制与辅助性T (Th) 17细胞和调节性T （Treg）细胞之间平衡的关系。方法：建立细菌感染所致慢性阻塞性肺病大鼠模型，连续12周口服白芍灵。然后处死大鼠，取肺组织进行组织学分析，取脾脏和肠系膜淋巴结（MLNs）检测Th17和Treg细胞。结果：口服白芍能明显抑制慢性阻塞性肺疾病的进展，减轻慢性阻塞性肺疾病的病理改变。它还降低了支气管肺泡灌洗液（BALF）中促炎细胞因子的水平，包括IL-1 β、IL-6、tnf - α和th17相关的IL-17A，并诱导treg相关的IL-10显著升高。此外，BYF治疗明显降低CD4(+)ROR γ t(+) t（Th17）细胞比例，增加CD4(+)CD25(+)Foxp3(+) t（Treg）细胞比例，恢复Th17/Treg平衡。BYF处理组也降低了ROR γ t，增加了脾脏和mln中Foxp3的表达。BYF进一步抑制了TH17和Treg分化的关键转录因子信号换能器和转录激活因子-3 （STAT3）的磷酸化，并促进了STAT5的磷酸化。结论：上述结果表明，黄芪丹参通过相互调节COPD大鼠体内STAT3和STAT5的活性，恢复Th17/Treg平衡，从而发挥其抗COPD的作用，这可能有助于阐明黄芪丹参对COPD治疗的潜在免疫调节模式。
Ethnopharmacology relevance: Bufei Yishen formula (BYF), a Traditional Chinese Medicine (TCM), has been extensively applied in clinical treatment of chronic obstructive pulmonary disease (COPD) and provides an effective treatment strategy for the syndrome of lung-kidney qi deficiency in COPD patients. Here, we investigated its anti-COPD mechanism in COPD rats in relation to the balance between T helper (Th) 17 cells and regulatory T (Treg) cells.Methods: Rat model of cigarette smoke- and bacterial infection-induced COPD was established, and orally treated with BYF for 12 consecutive weeks. Then, the rats were sacrificed, their lung tissues were removed for histological analysis, and spleens and mesenteric lymph nodes (MLNs) were collected to evaluate the Th17 and Treg cells.Results: Oral treatment of BYF markedly suppressed the disease progression and alleviated the pathological changes of COPD. It also decreased the bronchoalveolar lavage fluid (BALF) levels of pro-inflammatory cytokines, including IL-1 beta, IL-6, TNF-alpha and Th17-related IL-17A, and induced a significant increase in Treg-related IL-10. Furthermore, BYF treatment obviously decreased the proportion of CD4(+)ROR gamma t(+)T (Th17) cell and increased the proportion of CD4(+)CD25(+)Foxp3(+)T (Treg) cell, leading to restore the Th17/Treg balance. BYF treated groups also decreased ROR gamma t and increased Foxp3 expression in the spleens and MLNs. BYF further inhibited the phosphorylation of signal transducer and activator of transcription-3 (STAT3) and boosted the phosphorylation of STAT5, that were critical transcription factors for TH17 and Treg differentiation.Conclusion: these results demonstrated that BYF exerted its anti-COPD efficacy by restoring Th17/Treg balance via reciprocally modulating the activities of STAT3 and STAT5 in COPD rats, which may help to elucidate the underlying immunomodulatory mode of BYF on COPD treatment.