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中华肺部疾病杂志(电子版) ›› 2019, Vol. 12 ›› Issue (02) : 127 -141. doi: 10.3877/cma.j.issn.1674-6902.2019.02.001

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慢性阻塞性肺疾病的成因及其治疗的困惑与希望
任成山1, 王关嵩2,†(), 钱桂生2   
  1. 1. 400037　重庆，陆军军医大学（第三军医大学）新桥医院消化内科
    2. 400037　重庆，陆军军医大学（第三军医大学）新桥医院呼吸内科
  • 收稿日期:2019-02-11 出版日期:2019-04-20
  • 通信作者: 王关嵩
  • 基金资助:
    国家自然科学基金资助项目(81670047)

Nosogenesis of chronic obstructive pulmonary disease and the perplexity and hope of treatment

Chengshan Ren1, Guansong Wang2(), Guisheng Qian2   

  • Received:2019-02-11 Published:2019-04-20
  • Corresponding author: Guansong Wang
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任成山, 王关嵩, 钱桂生. 慢性阻塞性肺疾病的成因及其治疗的困惑与希望[J]. 中华肺部疾病杂志(电子版), 2019, 12(02): 127-141.

Chengshan Ren, Guansong Wang, Guisheng Qian. Nosogenesis of chronic obstructive pulmonary disease and the perplexity and hope of treatment[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2019, 12(02): 127-141.

图1 香烟烟雾初次应答导致COPD；注：TLR：Toll样受体；GM-CSF：粒细胞-巨噬细胞集落刺激因子；HSP：热休克蛋白；ICAM-1：细胞间黏附分子-1；MCP-1：单核细胞趋化蛋白-1；TNF-α：肿瘤坏死因子-α
图2 暴露于香烟烟雾后气道上皮连接的破坏；注：在香烟暴露在烟雾中，气道上皮细胞，特别是细胞间接触发生了显著变化。香烟烟雾可导致TJs的破坏，在磷酸化的ZO-1结合酪氨酸OCLN中的ZBR残留。此外，它还能降低ZO-1和OCLN的基因表达。香烟烟雾也能增加线粒体活性氧(ROS)的产生，而ROS反过来又会被激活表皮生长因子受体(EGFR)通过Src介导的ERK信号磷酸化。激活ERK可诱导TJ离解。此外，香烟烟雾还会破坏细胞与细胞之间的接触通过EGF和双调节蛋白(AREG)配体激活EGFR依赖的机制，以及EGFR独立的机制。此外，存在于香烟烟雾中的ROS可以诱导透明质酸裂解，通过其表面受体层林导致Rho激酶(岩石)磷酸化。岩石活化可以通过降低E-钙黏蛋白基因和蛋白表达来破坏AJs。AKAP：激酶锚定蛋白；CDH1：钙黏蛋白；CS：香烟；fHA：支离破碎的透明质酸；HI：透明质酸；Ub-Cbl：E3泛素连接酶。
图3 COPD与目前描述的包括哮喘在内的主要呼吸重叠综合征的中心地位的非比例维恩图，支气管扩张，纤维化和阻塞性睡眠呼吸暂停；注：慢性阻塞性肺疾病(COPD)，阻塞性睡眠呼吸暂停(OSA/OSAS)，哮喘-COPD重叠综合征、BCOS-支气管扩张症-COPD重叠综合征、FCOS-纤维化-COPD重叠综合征和OCOS-OSA-COPD重叠综合征，HRCT-高分辨率计算机断层扫描；ACOS：哮喘-COPD重叠综合征
图4 炎症微环境下启动STAT3与NF-κB的致癌作用；注：NF-κB: 核转录因子；IL-6：白细胞介素-6；COX-M: 环氧化酶；EGFR: 表皮生长因子受体；IGFR: 胰岛素样生长因子受体；VEGF: 血管内皮生长因子；HIF: 缺氧诱导因子STAT3: 信号转导与转录激活因子3；COPD：慢性阻塞性肺疾病
图5 GOLDⅠ-Ⅱ COPD患者管理治疗流程建议；注：COPD：慢性阻塞性肺疾病；ACOS或ACO：哮喘-COPD重叠综合征；LAMA：长效胆碱能拮抗剂；LABA：长效β-2受体激动剂；ICS：吸入型皮质类固醇；GOLD：全球慢性阻塞性肺疾病防治创议；mMRC dyspnea：呼吸困难量表
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