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American Journal of Respiratory Cell and Molecular Biology. Vol. 27, pp. 368-374, 2002
© 2002 American Thoracic Society
DOI: 10.1165/rcmb.4791

Acute Cigarette Smoke–Induced Connective Tissue Breakdown Requires both Neutrophils and Macrophage Metalloelastase in Mice

Andrew Churg, Katalin Zay, Selena Shay, Changshi Xie, Steven D. Shapiro, Robert Hendricks and Joanne L Wright

Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada; Roche Bioscience, Palo Alto, California; and Department of Respiratory Medicine, Brigham and Women's Hospital, Boston, Massachusetts

Address correspondence to: Andrew Churg, M.D., Department of Pathology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5 Canada. E-mail: achurg{at}interchange.ubc.ca

The cells/proteases responsible for the development of smoke-induced emphysema is an area of intense investigation. Mice with knockout of macrophage metalloelastase genes (MME-/-) do not develop emphysema after smoke exposure, but we also observed that neutrophils (PMN) in lavage appeared to be a requirement for acute connective tissue breakdown. In this study we exposed mice to cigarette smoke and examined lavage PMN, macrophages (MAC), desmosine (DES, a measure of elastin breakdown) and hydroxyproline (HP, a measure of collagen breakdown) 24 h afterwards. MME+/+ mice exposed to smoke showed elevations in PMN, DES, and HP, but no elevations were seen in MME-deficient mice. Both PMN influx and increased levels of DES/HP could be restored by administering MAC from MME+/+ mice to MME-deficient mice and then exposing them to smoke. RS113456, a metalloprotease inhibitor, also prevented PMN influx and connective tissue breakdown. Western blots against mouse {alpha}1-antitrypsin ({alpha}1AT) showed that {alpha}1AT was not protected in MME-deficient mice, nor by administration of RS113456. We conclude that, in mice, acute smoke-induced connective tissue breakdown, the precursor to emphysema, requires both PMN and MME, that PMN influx appears to be secondary to MAC activation, and that this process initially does not involve protection of {alpha}1AT from metalloprotease attack.

Abbreviations: {alpha}1 antitrypsin, {alpha}1AT • aminoethyl benezenesulfonyl fluoride, AEBSF • desmosine, DES • hydroxyproline, HP • macrophages, MAC • macrophage metalloelastase, MME • neutrophils, PMN • tris-buffered saline, TBS • tris-buffered saline with Tween 20, TBST




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