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Published ahead of print on April 10, 2003, doi:10.1164/rccm.200302-203OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 199-207, (2003)
© 2003 American Thoracic Society

Original Article

{alpha}-1-Antitrypsin Ameliorates Cigarette Smoke–induced Emphysema in the Mouse

Andrew Churg, Rong D. Wang, Changshi Xie and Joanne L. Wright

Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to Andrew Churg, M.D., Department of Pathology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5. E-mail: achurg{at}interchange.ubc.ca

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.

Key Words: neutrophil • {alpha}-1-antitrypsin • cigarette smoke • emphysema




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