气道上皮细胞岩藻糖基化的应答障碍引发菌群失衡--COPD急性加重新机制

Viral infection induces airway dysbiosis and airway inflammation, which is recognized as the main pathogenesis of the acute exacerbation of COPD (AECOPD). The dysfunctional IL-22/IL-22R axis is an important mechanism of immune defence impairment after virus infection in COPD. It has been demonstrated that epithelial cells fucosylation regulated by IL-22/IL-22R axis is crucial to maintain gut microbiota homeostasis. We have shown that the levels of IL-22 and epithelial cell fucosylation both elevated after the nasal stimulation of poly(I:C) in mice. Therefore, the IL-22/IL-22R axis dysfunction leading to an impaired fucosylation in airway epithelial cells, which results in the airway dysbiosis and airway inflammation, might be the important pathogenic mechanism of AECOPD. This project will ① investigate the difference in levels of the key moleculars in the IL-22/IL-22R axis mediated epithelial cell fucosylation pathway in induced sputum of AECOPD patients, and correlate with airway microbiota and airway inflammation; ② use the IL22RA1 gene silenced human bronchial epithelial cells and IL22RA1 gene knock-out mice to demonstrate the IL-22/IL-22R axis-mediated epithelial fucosylation pathway and its effects on airway microbiota and airway inflammation; ③ use cigarette smoke extra and cathepsin G induced COPD related cell injury model as well as chronic smoke exposed mice model to demonstrate the crucial role of the IL-22/IL-22R axis-mediated epithelial fucosylation pathway in airway dysbiosis and airway inflammation after viral infection in COPD. This study will help to provide novel target for precise treatment for COPD.

病毒感染引发气道菌群失衡及气道炎症是COPD急性加重（AECOPD）的主要病理生理机制，而IL-22/IL-22R轴功能失调是COPD病毒感染后免疫防御受损的关键。研究证实该轴调控的上皮细胞岩藻糖基化修饰在维持肠道菌群平衡中至关重要。我们发现病毒类似物经鼻刺激后小鼠气道IL-22和上皮岩藻糖基化水平同步上调。因此IL-22/IL-22R轴功能失调导致病毒感染后气道上皮细胞岩藻糖基化应答障碍，引发菌群失衡及炎症，可能是AECOPD的重要病理机制。本课题拟通过①临床诱导痰研究明确AECOPD中上皮岩藻糖基化通路关键分子的差异表达及与菌群、炎症的关系；②IL22R1基因沉默和条件敲除明确IL-22/IL-22R轴对岩藻糖基化的调控机制及对气道菌群、炎症的影响；③COPD相关上皮细胞模型和烟熏小鼠模型研究证实该通路在COPD病毒感染后菌群失衡和炎症中的关键作用，为AECOPD精准治疗提供新靶点。

病毒感染引发气道菌群失衡及气道炎症是COPD急性加重(AECOPD)的主要病理生理机制， 而IL-22/IL-22R轴功能失调是COPD病毒感染后免疫防御受损的关键。研究证实IL-22/IL-22R轴调控的上皮细胞岩藻糖基化修饰在维持肠道菌群平衡中至关重要。我们的前期研究发现病毒类似物经鼻刺激后小鼠气道IL-22和上皮岩藻糖基化水平同步上调,IL-22/IL-22R轴功能失调导致病毒感染后气道上皮细胞岩藻糖基化应答障碍，引发菌群失衡及炎症，可能是AECOPD的重要病理机制。本课题通过临床研究首先证实FUT2基因型与人气道上皮岩藻糖基化表达间的对应关系，其后通过诱导痰研究证实COPD患者气道上皮细胞岩藻糖基化是急性加重风险的独立影响因素。岩藻糖基化表达影响患者气道菌群⍺和β多样性，以及特定菌群丰度上存在显著差异。微生物共线性网络分析表明岩藻糖基化不表达患者气道菌群相互作用网络复杂度降低且微生物共线性网络的度中心性、紧密中心性及集聚系数均显著降低。同时，岩藻糖基化表达患者气道IL-18及 IL-6等炎症水平上调。动物实验数据显示LPS/poly:IC刺激均上调FUT2基因、引起上皮岩藻糖基化表达，通过IL22ra1-/-和FUT2-/-敲除小鼠模型我们发现IL-22介导FUT2通路影响AECOPD模型和ALI模型小鼠气道菌群结构和气道炎症水平，气道内补充L-fucose可通过改善气道菌群发挥抗炎作用。以上临床与基础研究结果提示气道上皮细胞岩藻糖基化通过介导气道菌群和气道炎症参与COPD急性加重机制，在国内外首次揭示气道上皮岩藻糖基化在COPD和ALI中的确切机制，补充气道益生元L-fucose可改善气道菌群发挥抗炎作用，为制定COPD创新临床治疗策略，减少COPD急性加重、减轻气道炎症提供了科学依据。

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