Emphysema, which with chronic bronchitis accounts for model of emphysema initiated by blockade of vascular endothelial growth factor (VEGF) receptors (8), Aoshiba most of the chronic obstructive pulmonary diseases (COPD), is defined as “a condition of the lung characterized by abnor- and colleagues asked whether directly-induced alveolar cell apoptosis suffices to trigger emphysema. By using an amphimal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of their walls, pathic reagent to transport proteins into bronchial epithelial cells in vivo, Aoshiba and coworkers showed that intrabronwith or without obvious fibrosis”(1). The concepts of permanent and destruction are critical in this definition, as they chial delivery of active caspase 3 or nodularin (a serine/threonine kinase inhibitor) caused alveolar apoptosis and convey the unique and characteristic distinguishing features of a disease process ultimately leading to the disappearance emphysema that started as early as 2 h after instillation. Whereas alveolar apoptosis was no longer evident 6 h after of lung tissue. Over the past 30 years, inflammation and a protease/antiprotease imbalance have been proposed to act instillation, morphometrically detectable and physiologically significant airspace enlargement persisted for at least as downstream effectors of the lung destruction following chronic cigarette smoking, which accounts for 95% of cases 15 d, followed by gradual recovery. Remarkably, this approach did not cause inflammation or other forms of lung of emphysema. Accordingly, emphysema study designs relied on determining whether a specific experimental ap- pathology. Although one may prematurely suggest that intrabronchial instillation of an apoptotic agent is “unphysioproach aimed at exposing animals to chronic cigarette smoke, lung inflammation, or proteolytic destruction of alveolar logic,” the 5,000 plus chemical compounds and in excess of 10 (15) free radical molecules present in the cigarette smoke matrix caused or did not cause emphysema (2). However, the emphasis on alveolar matrix destruction can directly trigger several of the molecular pathways involved in the apoptosis process (Figure 2). Piecing together by the combination of inflammation and excessive proteolysis has failed to fully account for the mechanisms behind the pathobiologically relevant processes and using reductionist approaches such as that of Aoshiba and associates will allow eradication of septal structures (3) and the unique nature of lung destruction as compared with alterations seen in other us to revisit chronic cigarette smoke models to better underinflammatory lung diseases. For example, the downstream stand the uniqueness of the destructive process in emphyconsequences and the direct injury to alveolar cells by com- sema. It is becoming progressively apparent that excessive ponents of cigarette smoke have received much less atten- proteolysis, lung cell apoptosis, and oxidative stress interact tion. It is in this context that the contribution of the work as means by which the lung is destroyed in emphysema. of Aoshiba and coworkers should be analyzed (4). The observations noted above raise several important Building on a recent paradigm that highlights the pres- questions about the lung responses to injury and the relation ence of apoptosis in human emphysematous lungs (5–7) between lung apoptosis and emphysema. Most striking is (Figure 1) and the causal role of apoptosis in an animal the rapidity and extent with which the structural alterations appeared after the transfer of active caspase 3 or nodularin to 3% of cells, as assessed by …