Pitfalls in antiprotease therapy of emphysema.
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.
Pulmonary Section, Boston Veterans Administration Medical Center Massachusetts.
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GL
Snider
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Lucey
P J
PJ
Stone
D000818:Animals; D001897:Boronic Acids / Q000627:therapeutic use; D004549:Elastin / Q000378:metabolism; D006801:Humans; D019272:Leukocyte Elastase; D008168:Lung / Q000201:enzymology; D009842:Oligopeptides / Q000627:therapeutic use; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*
D001897:Boronic Acids; D009842:Oligopeptides; D011480:Protease Inhibitors; D004549:Elastin; C048437:methyl-O-succinyl-alanyl-alanyl-prolyl-borovaline-pinacol; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase