Many individuals with
emphysema are unable to stop smoking despite the best efforts of specialists in smoking cessation. Because
emphysema is a slowly progressive disease, it is rational to attempt to develop drugs for it. The hope is that
drug therapy will slow the rate of decline of lung function, thereby delaying the onset of disability and prolonging life. The major emphasis in
drug development has been on
antiproteases having the ability to inhibit
neutrophil elastase. There are a number of potential pitfalls in the development of such drugs. Although there is gathering evidence that
elastin degradation is a part of the development of human
emphysema, it is evident from studies in experimental
emphysema that
protease-
antiprotease imbalance is not the only pathogenetic mechanism that gives rise to
emphysema. There is strong evidence that human centrilobular and
panacinar emphysema are different in pathogenesis. Indeed, airspace enlargement may be considered one of the stereotyped ways that the lung heals after a variety of
injuries. There is accumulating evidence that macrophages as well as neutrophils may participate in elastolysis;
antiproteases designed to inhibit
neutrophil elastase may not inhibit the
metalloproteases produced by macrophages. Some
antiproteases may serve to transport
elastase into the interstitium of the lung and actually increase the risk of
emphysema. A process study of
antiprotease therapy, using a measure of alteration of
elastase burden of the lungs and urinary
elastin peptides and
desmosine measurements as markers of
elastin degradation is now feasible. An outcome study of
antiprotease therapy of
emphysema should not be undertaken unless there is evidence from a process study that an
antiprotease has biochemical efficacy and no unacceptable side effects.