In respiratory tract infections, leukocytes are recruited to the lungs
, where they help remove invading organisms through phagocytic clearan
ce. In some instances, however, the normal inflammatory response may b
e as destructive as it is defensive. The neutrophils secrete a proteol
ytic enzyme, neutrophil elastase, which has emerged as a major culprit
in the pathogenesis of inflammatory airway disease. This enzyme has b
een found to strip the bronchial epithelium, reduce ciliary beating, a
nd stimulate excess mucus secretion, leading to mucus retention, bacte
rial proliferation, and recurrent infections. Neutrophil elastase also
stimulates epithelial cell interleukin-8 secretion and produces other
chemoattractant cleavage products that lead to further neutrophil rec
ruitment. It also impairs host defenses by damaging the major opsonoph
agocytic receptor on the neutrophil and by weakening the efficacy of i
mmunoglobulins. For this reason, an important goal in the treatment of
respiratory tract infections should be to prevent or shorten the dura
tion of neutrophil elastase release. A number of different approaches
have been proposed or attempted in an effort to modulate the proteinas
e burden. These include direct inhibition of elastase and interference
with the recruitment, adherence, and degranulation of neutrophils. An
even more fundamental approach would start in the bone marrow, where
attempts might be made to modulate or modify neutrophil precursors so
as to limit the destructive potential of the mature neutrophils.