(A) Initiation: Environmental agents trigger host cell responses, largely dominated by inflammation and oxidative stress. RTP801 is activated by cigarette smoke, largely due to oxidants, mediating inflammatory responses, oxidative stress, and alveolar cell death. DAMPs and PAMPs present in tobacco or generated endogenously may further enhance pathologic responses. Nrf2, by activating a host of antioxidant mediators, protects the lung and may promote lung repair processes. (B) Progression: Cigarette smoke disrupts alveolar maintenance, triggering apoptosis and autophagy; moreover, oxidants in tobacco and activated inflammatory and alveolar cells lead to extracellular matrix proteolysis, which further enhances inflammation and promote a feedback loop with apoptosis. Several of these interactions are facilitated by decreased expression of trophic/maintenance factors and endogenous mediators of alveolar destruction, including ceramide and EMAPII. (C) Consolidation: Over decades of exposure to cigarette smoke and endogenous amplifiers of destructive processes, there is progressive lung aging, with autoinflammatory stimuli generated through self-antigens or microbial/viral agents. TH17-positive cells, which are increased in COPD patients, may mediate the autoimmunity process. Macromolecular damage may lead to progressive telomere erosion and activation of p21^{CIP1/WAF1/SDI1} as part of the cell senescence response, which together may lead to a terminally injured lung.