The first recognized animal model of emphysema was reported in 1964 as a surprising outcome following instillation of the metalloproteinase papain in the lungs. The concept that a proteolytic enzyme could induce emphysema fitted well with the prevalence of emphysema in AATD. The demonstration that human neutrophil elastase7 and proteinase 3,55 both serine proteinases, are capable of inducing an “emphysematous” phenotype in experimental animals seemed to close the loop. Lung elastin is a stable long-lived tissue in healthy humans,56 and the link between cutis laxa and emphysema57 supports elastin as being central to the emphysematous process. The proteolytic target was reasonably deemed to be lung elastin, and this was supported by studies showing that loss of lung elastin followed by rapid accumulation of nonfibrillary elastin58 loss due to starvation,59 prevention of elastin cross-linking,60 and other classes of enzymes capable of digesting elastin61 produced the same pathologic changes. Indeed, the demonstration that the interstitial NE signal related to the amount of emphysema in humans62 provided further supportive evidence of the NE pathway. Transgenic models overexpressing inflammatory cytokines63 and several knock-out mouse models64,65 added to the knowledge implicating inflammation, neutrophils, macrophages, metalloproteinases, autoimmunity, cell death, and tissue damage/repair in a complex cascade of events, all of which have received some credence from human studies and have been the subject of many reviews.66,67 However, the implication of many individual components reflects such complex interactions that it remains difficult to identify any one key step or process in human disease. It may be that there are many pathways leading to one central end point, but dissecting physiologic from pathologic response remains a major challenge while studying the inflammatory processes involved.