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Published ahead of print on April 10, 2003, doi:10.1164/rccm.200302-203OC

Am. J. Respir. Crit. Care Med., Volume 168, Number 2, July 2003, 199-207

A more recent version of this article appeared on July 15, 2003
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Submitted on February 13, 2003
Accepted on April 7, 2003

Alpha-1-Antitrypsin Ameliorates Cigarette Smoke-Induced Emphysema In The Mouse

Andrew Churg1*, Rong D Wang1, Changshi Xie1, and Joanne L Wright1

1 Pathology, University of British Columbia, Vancouver, BC, Canada

* To whom correspondence should be addressed. 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 the present experiments we utilized 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 20mg human A1AT (Prolastin) every 48 hours. Treatment with A1AT produced an approximately 2 fold 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 anti-inflammatory mechanism related to tumor necrosis factor-{alpha} suppression, and provides partial protection against emphysema.
Key words: emphysema, neutrophil, alpha-1-antitrypsin, cigarette smoke, TNF-alpha




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