It is clear that alpha 1AT deficiency leads to early onset
pulmonary emphysema. With the lead provided by the deficiency state, studies aimed at the linkage between alpha 1AT and its target
enzyme,
neutrophil elastase, have provided useful information about the pathogenesis of
emphysema due to cigarette smoking. alpha 1AT represents the predominant antielastase of the lower respiratory tract. This observation implicates
neutrophil elastase as the
enzyme responsible for lung destruction, since affinity studies demonstrate that alpha 1ATs physiologically relevant function is the inhibition of
neutrophil elastase. However, because of the inexorably slow nature of the
emphysema process, demonstration of the
protease-
antiprotease imbalance in the lungs of smokers has been difficult. Studies using sensitive assays for alpha 1AT function and for
neutrophil elastase's presence have added new support for the
protease-
antiprotease theory, and evaluation of related disorders such as the
adult respiratory distress syndrome and
cystic fibrosis have provided corraborative evidence. Finally, studies that have indicated that the major site of the
protease-
antiprotease imbalance is the microenvironment of
protease-producing cells offer a new direction for future research into the pathogenesis of
emphysema.