Tokyo Medical University Ibaraki Medical Center, Ibaraki.
Eur Respir J. 2013 Dec;42(6):1689-95. doi: 10.1183/09031936.00102912. Epub 2013 Feb 8.
Inflammation in chronic obstructive pulmonary disease (COPD) is thought to originate from the activation of innate immunity by a danger signal (first hit), although this mechanism does not readily explain why the inflammation becomes chronic. Here, we propose a two-hit hypothesis explaining why inflammation becomes chronic in patients with COPD. A more severe degree of inflammation exists in the lungs of patients who develop COPD than in the lungs of healthy smokers, and the large amounts of reactive oxygen species and reactive nitrogen species released from inflammatory cells are likely to induce DNA double-strand breaks (second hit) in the airways and pulmonary alveolar cells, causing apoptosis and cell senescence. The DNA damage response and senescence-associated secretory phenotype (SASP) are also likely to be activated, resulting in the production of pro-inflammatory cytokines. These pro-inflammatory cytokines further stimulate inflammatory cell infiltration, intensifying cell senescence and SASP through a positive-feedback mechanism. This vicious cycle, characterised by mutually reinforcing inflammation and DNA damage, may cause the inflammation in COPD patients to become chronic. Our hypothesis helps explain why COPD tends to occur in the elderly, why the inflammation worsens progressively, why inflammation continues even after smoking cessation, and why COPD is associated with lung cancer.
在慢性阻塞性肺疾病（COPD）中，炎症被认为起源于固有免疫被危险信号激活（第一击），尽管这一机制并不能很好地解释为什么炎症会变成慢性。在这里，我们提出了一个两击假说，解释为什么 COPD 患者的炎症会变成慢性。与健康吸烟者的肺部相比，发展为 COPD 的患者肺部存在更严重程度的炎症，并且炎症细胞释放的大量活性氧和活性氮物种可能会导致气道和肺泡细胞中的 DNA 双链断裂（第二击），从而引起细胞凋亡和衰老。DNA 损伤反应和衰老相关分泌表型（SASP）也可能被激活，导致促炎细胞因子的产生。这些促炎细胞因子进一步刺激炎症细胞浸润，通过正反馈机制加剧细胞衰老和 SASP。这种以相互增强的炎症和 DNA 损伤为特征的恶性循环可能导致 COPD 患者的炎症持续存在。我们的假说有助于解释为什么 COPD 倾向于发生在老年人中，为什么炎症逐渐恶化，为什么即使在戒烟后炎症仍持续存在，以及为什么 COPD 与肺癌有关。
