title: The danger signal plus DNA damage two-hit hypothesis for chronic inflammation in COPD.
abstract: 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.
authors: Tokyo Medical University Ibaraki Medical Center, Ibaraki.
authors: Kazutetsu
authors: K
authors: Aoshiba
authors: Takao
authors: T
authors: Tsuji
authors: Kazuhiro
authors: K
authors: Yamaguchi
authors: Masayuki
authors: M
authors: Itoh
authors: Hiroyuki
authors: H
authors: Nakamura
mesh_terms: D000818:Animals; D017209:Apoptosis; D016922:Cellular Senescence / Q000235:genetics; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D018384:Oxidative Stress; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000503:physiopathology*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D016540:Smoking Cessation
chemical_list: D016207:Cytokines; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species