A review of the recent basic experimental approach to emphysema reveals another potential connection to the report of Mulgrew et al and the misfolding concept. It appears that targeting virtually any gene to the lung epithelium can induce emphysema (eg, IL-11,15platelet-derived growth factor,16IL-6,17IL-13,18interferon-γ,19tumor necrosis factor-α,20and transforming growth factor-α21). Perhaps any one of these transgenic proteins can disrupt the inflammatory balance to an extent that results in lung injury and destruction. However, when viewed from the context of the report by Mulgrew et al, another interpretation might also be entertained. Perhaps these lung-targeted transgenic proteins are dysregulated in quantity or quality such that they aggregate in the lung epithelium, producing lung injury. Thus, it seems reasonable to hypothesize that PiZ-related emphysema may arise at least in part from chronic injury to lung epithelial cells as a result of locally aggregated α1-antitrypsin. Contributing further to the injury is the ability of the aggregated PiZ protein to attract neutrophils. Perhaps, some individuals are more predisposed to induce misfolded protein as a result of differences in chaperonins or differences in environmental exposures that trigger epithelial cells to produce increased amounts of α1-antitrypsin. Indeed, PiZ emphysema may target the lung bases simply because basilar epithelial cells get more of the exposures that trigger increased local α1-antitrypsin production with resultant aggregation of protein.