Serine elastase inhibitors have been proposed as a treatment for cigarette
smoke-induced
emphysema, but little is known about whether such agents actually are effective. We recently reported that a synthetic
serine elastase inhibitor, ZD0892, provided some protection against
emphysema in a guinea pig model. For these experiments, we used transgenic mice that expressed extremely low levels of human alpha-1-antitrypsin (A1AT) but were tolerant of exogenous human A1AT. Mice were exposed to daily cigarette
smoke for up to 6 months; some animals received 20 mg of human A1AT (
Prolastin) every 48 hours. Treatment with A1AT produced an approximate twofold increase in serum A1AT levels and
elastase inhibitory capacity and abolished
smoke-induced elevations in lavage neutrophils and matrix breakdown products (
desmosine and
hydroxyproline) measured from 2 to 30 days of
smoke exposure. A1AT oxidized to remove antiproteolytic activity did not increase serum
elastase inhibitory capacity but did prevent neutrophil influx. Treatment with A1AT for 6 months provided 63% protection against increased airspace size (
emphysema) and abolished
smoke-mediated increases in plasma
tumor necrosis factor-alpha. We conclude that A1AT
therapy ameliorates
smoke-induced
inflammation and matrix breakdown, possibly via an antiinflammatory mechanism related to
tumor necrosis factor-alpha suppression, and provides partial protection against
emphysema.