Two-hit hypothesis, consisting of a danger signal plus DNA damage, explaining chronic inflammation in chronic obstructive pulmonary disease (COPD). a) In smokers, the danger signal (hit 1) is the trigger initiating inflammation in the lungs (the hypothesis of Cosio et al. [1]). According to the two-hit hypothesis, “susceptible” smokers who are predisposed to COPD develop DNA damage (hit 2), which induces apoptosis and senescence and activates the DNA damage response (DDR) and senescence-associated secretory phenotype (SASP), leading to the production of pro-inflammatory cytokines. b) Unlike healthy smokers, “susceptible” smokers develop DNA damage (e.g. double-strand breaks) in the airways and alveolar cells, presumably because of severer inflammatory cell infiltration and larger amounts of reactive oxygen species (ROS)/ reactive nitrogen species (RNS) production, a less efficient induction of antioxidants, and/or more inefficient DNA repair mechanisms. This, in turn, results in the activation of the DDR, apoptosis, senescence, and SASP and the production of pro-inflammatory cytokines. The pro-inflammatory cytokines then intensify inflammatory cell infiltration, forming a positive-feedback loop that further induces ROS/RNS production and the activation of the DDR, apoptosis, senescence, and SASP. In this manner, a vicious cycle is established between inflammation and DNA damage, and the inflammation becomes chronic. DAMP: damage-associated molecular pattern; IL: interleukin.