TY - JOUR T1 - The danger signal plus DNA damage two-hit hypothesis for chronic inflammation in COPD JF - European Respiratory Journal JO - Eur Respir J SP - 1689 LP - 1695 DO - 10.1183/09031936.00102912 VL - 42 IS - 6 AU - Kazutetsu Aoshiba AU - Takao Tsuji AU - Kazuhiro Yamaguchi AU - Masayuki Itoh AU - Hiroyuki Nakamura Y1 - 2013/12/01 UR - http://erj.ersjournals.com/content/42/6/1689.abstract N2 - 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. A vicious cycle, involving mutually reinforcing inflammation and DNA damage, may cause chronic inflammation in COPD http://ow.ly/nYW4u ER -