Although our preclinical studies suggest a more prominent role for IL-1α in driving neutrophilic inflammation, recent works by Eltom et al,85 and Lucattelli et al86 suggest a potential role for DAMPs, such as extracellular sources of adenosine triphosphate (ATP), in driving neutrophilic inflammation. This is of particular interest since ATP has been shown to be increased in the lungs of patients with COPD.87 Excess levels of ATP are proposed to activate the purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7) receptor, which, in turn, activates both the inflammasome and caspase-1. The study by Eltom et al85 demonstrated in P2X7-deficient mice that cigarette smoke failed to increase airway neutrophilia, caspase-1 activity, and IL-1β compared with the relevant wild-type control mice. Although the authors elegantly demonstrated that a P2X7 inhibitor could block cigarette-smoke induced inflammation, they did not assess whether a P2X7 deficiency altered IL-1α levels. Importantly, the study by Lucattelli et al86 demonstrated further that emphysema was attenuated in P2X7-deficient animals compared with control animals. Of particular interest was the finding that P2X7 receptor expression was essential on immune cells in chimeric mouse experiments because they demonstrated that an immune cell deficiency in P2X7 attenuated lung inflammation and emphysema in smoke-exposed mice. Interestingly, HMGB-1 (high-mobility group protein 1), another DAMP molecule, has been shown to be elevated in COPD airways88 and could also be explored along with other DAMPs for their potential in mediating the mechanisms of IL-1α/IL-1R1 neutrophilic inflammation. Furthermore, although accumulating evidence suggests that the sterile inflammatory response is playing a role in cigarette smoke-induced inflammation, a more in-depth analysis of these pathways is warranted because these mechanisms may provide a rationale for the design of novel pharmacotherapies.