Rapamycin attenuates Tc1 and Tc17 cell responses in cigarette smoke-induced emphysema in mice
Rapamycin attenuates Tc1 and Tc17 cell responses in cigarette smoke-induced emphysema in mice
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雷帕霉素减弱香烟烟雾引起的小鼠肺气肿中 Tc1 和 Tc17 细胞的反应
DOI：
10.1007/s00011-019-01278-0
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发表时间：
2019
影响因子：
6.7
通讯作者：
Zhong Xiaoning
中科院分区：
文献类型：
--
作者：
Zhang Hui;Zhou Xiu;Chen Xin;Lin Yuanzhen;Qiu Shilin;Zhao Yun;Tang Qiya;Liang Yi;Zhong Xiaoning
目的与设计慢性香烟烟雾暴露可促进气道炎症和肺气肿，并伴有CD 8+干扰素（IFN）-γ+T（Tc 1）和CD 8+白细胞介素（IL）-17+T（Tc 17）细胞应答增强。哺乳动物雷帕霉素靶蛋白（mTOR）参与肺气肿的发病机制。据报道，通过雷帕霉素抑制mTOR可以缓解肺气肿，但其机制尚未完全了解。本研究旨在探讨雷帕霉素对香烟烟雾暴露诱导的Tc 1和Tc 17细胞反应的影响。在过去的12周里，一半的烟雾暴露小鼠接受了雷帕霉素。以平均肺动脉截距（MLI）、平均肺泡气面积（MAA）和肺损伤指数（DI）评价肺气肿的严重程度。收集支气管肺泡灌洗液并进行分析。流式细胞术检测CD 8 +T细胞、Tc 1和Tc 17细胞中磷酸化（p-）mTOR的表达。Western blot分析肺组织中p-mTOR的相对表达。采用酶联免疫吸附试验检测IFN-γ和IL-17 A水平。结果香烟烟雾暴露小鼠肺组织和CD 8 +T细胞中p-mTOR表达增强，同时肺组织中Tc 1和Tc 17细胞反应增强。雷帕霉素减少支气管肺泡灌洗液中的炎症细胞，降低肺中的MLI、DI和MAA。结论香烟烟雾诱导的肺气肿小鼠肺组织炎症反应中，CD 8 +T细胞mTOR被激活，同时伴有Tc 1和Tc 17细胞反应增强。雷帕霉素改善肺气肿和衰减Tc 1和Tc 17细胞反应可能是由于抑制mTOR在香烟烟雾暴露的小鼠。
Objective and designChronic exposure to cigarette smoke promotes airway inflammation and emphysema accompanied by enhanced CD8+interferon (IFN)-γ+T(Tc1) and CD8+interleukin (IL)-17+T(Tc17) cell responses. The mammalian target of rapamycin (mTOR) has been involved in the pathogenesis of emphysema. Inhibiting mTOR by rapamycin has been reported to alleviate emphysema, but the mechanism is not fully understood. We aimed to explore the effect of rapamycin on Tc1 and Tc17 cell responses induced by cigarette smoke exposure.MaterialsMale C57BL/6 mice were exposed to cigarette smoke or room air for 24 weeks. Half of the smoke-exposed mice received rapamycin in the last 12 weeks. The severity of emphysema in those mice was evaluated by mean linear intercept (MLI), mean alveolar airspace area (MAA) and destructive index (DI). Bronchoalveolar lavage was collected and analyzed. Phosphorylated (p-) mTOR in CD8+T cells, Tc1 and Tc17 cells were detected by flow cytometry. The relative expression of p-mTOR in lungs was determined by western blot analysis. IFN-γ and IL-17A levels were detected by enzyme-linked immunosorbent assays. IFN-γ, mTOR and RAR-related orphan receptor (ROR)γt mRNA levels were evaluated by the real-time polymerase chain reaction.ResultsElevated p-mTOR expression in CD8+T cells and lung tissue was accompanied by the enhanced Tc1 and Tc17 cell responses in lungs of mice exposed to cigarette smoke. Rapamycin reduced inflammatory cells in BALF and decreased MLI, DI and MAA in lungs. Rapamycin decreased p-mTOR expression, and down-regulation of mTOR and RORγt mRNA levels along with the attenuation of Tc1 and Tc17 cell responses in mice with emphysema.ConclusionsThe mTOR was activated in CD8+T cells accompanied by the enhanced Tc1 and Tc17 cell responses in cigarette smoke-related pulmonary inflammation. Rapamycin ameliorated emphysema and attenuated Tc1 and Tc17 cell responses probably caused by inhibiting mTOR in cigarette smoke-exposed mice.