Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, China.
Inflamm Res. 2019 Nov;68(11):957-968. doi: 10.1007/s00011-019-01278-0. Epub 2019 Aug 29.
Chronic 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.
Male 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.
Elevated 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.
The 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.
慢性暴露于香烟烟雾会促进气道炎症和肺气肿，同时伴有增强的 CD8 干扰素（IFN）-γ T（Tc1）和 CD8 白细胞介素（IL）-17 T（Tc17）细胞反应。雷帕霉素靶蛋白（mTOR）已参与肺气肿的发病机制。据报道，通过雷帕霉素抑制 mTOR 可以减轻肺气肿，但机制尚不完全清楚。我们旨在探讨雷帕霉素对香烟烟雾暴露诱导的 Tc1 和 Tc17 细胞反应的影响。
雄性 C57BL/6 小鼠暴露于香烟烟雾或室内空气 24 周。一半的烟雾暴露小鼠在最后 12 周接受雷帕霉素治疗。通过平均线性截距（MLI）、平均肺泡空气空间面积（MAA）和破坏性指数（DI）评估这些小鼠肺气肿的严重程度。收集支气管肺泡灌洗液并进行分析。通过流式细胞术检测 CD8 T 细胞、Tc1 和 Tc17 细胞中磷酸化（p-）mTOR 的表达。通过 Western blot 分析确定肺中 p-mTOR 的相对表达。通过酶联免疫吸附试验检测 IFN-γ 和 IL-17A 水平。通过实时聚合酶链反应评估 IFN-γ、mTOR 和视黄酸受体相关孤儿受体（ROR）γt mRNA 水平。
香烟烟雾暴露小鼠的 CD8 T 细胞中 mTOR 表达升高，同时伴有肺 Tc1 和 Tc17 细胞反应增强。雷帕霉素减少了 BALF 中的炎症细胞，并降低了肺部的 MLI、DI 和 MAA。雷帕霉素降低了 p-mTOR 表达，并下调了 mTOR 和 RORγt mRNA 水平，同时减弱了肺气肿小鼠的 Tc1 和 Tc17 细胞反应。
mTOR 在 CD8 T 细胞中被激活，同时伴有香烟烟雾相关肺炎症中的 Tc1 和 Tc17 细胞反应增强。雷帕霉素改善了肺气肿，并减轻了 Tc1 和 Tc17 细胞反应，可能是通过抑制香烟烟雾暴露小鼠中的 mTOR 引起的。
