Gl. Snider et al., PITFALLS IN ANTIPROTEASE THERAPY OF EMPHYSEMA, American journal of respiratory and critical care medicine, 150(6), 1994, pp. 190000131-190000137
Citations number
52
Categorie Soggetti
Emergency Medicine & Critical Care","Respiratory System
Many individuals with emphysema are unable to stop smoking despite the
best efforts of specialists in smoking cessation. Because emphysema i
s a slowly progressive disease, it is rational to attempt to develop d
rugs for it. The hope is that drug therapy will slow the rate of decli
ne of lung function, thereby delaying the onset of disability and prol
onging life. The major emphasis in drug development has been on antipr
oteases having the ability to inhibit neutrophil elastase. There are a
number of potential pitfalls in the development of such drugs. Althou
gh there is gathering evidence that elastin degradation is a part of t
he development of human emphysema, it is evident from studies in exper
imental 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 differen
t in pathogenesis. Indeed, airspace enlargement may be considered one
of the stereotyped ways that the lung heals after a variety of injurie
s. There is accumulating evidence that macrophages as well as neutroph
ils may participate in elastolysis; antiproteases designed to inhibit
neutrophil elastase may not inhibit the metalloproteases produced by m
acrophages. Some antiproteases may serve to transport elastase into th
e interstitium of the lung and actually increase the risk of emphysema
. A process study of antiprotease therapy, using a measure of alterati
on of elastase burden of the lungs and urinary elastin peptides and de
smosine 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 antip
rotease has biochemical efficacy and no unacceptable side effects.