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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 954-960, (2002)
© 2002 American Thoracic Society

Original Articles

Synthetic Serine Elastase Inhibitor Reduces Cigarette Smoke–induced Emphysema in Guinea Pigs

Joanne L. Wright, Stephen G. Farmer and Andrew Churg

Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada; and Department of Biosciences, AstraZeneca R&D, Lund, Sweden

Correspondence and requests for reprints should be addressed to J.L. Wright, M.D., Department of Pathology, University of British Columbia, Vancouver, BC, V6T 2B5 Canada. E-mail: jlwright{at}interchange.ubc.ca

To test whether a serine elastase inhibitor could prevent or reduce emphysema, we exposed guinea pigs to cigarette smoke acutely, or daily for 6 months, and treated some animals with the neutrophil elastase inhibitor ZD0892. Acute smoke exposure increased lavage neutrophils and increased desmosine and hydroxyproline, measures of elastin and collagen breakdown; all these measures were reduced by ZD0892. Long-term smoke exposure produced emphysema and increases in lavage neutrophils, desmosine, hydroxyproline, and plasma tumor necrosis factor {alpha} (TNF-{alpha}). ZD0892 treatment returned lavage neutrophils, desmosine, and hydroxyproline levels to control values, and decreased airspace enlargement by 45% and TNF-{alpha} by 30%. Animals exposed to smoke for 4 months and then to smoke plus ZD0892 for 2 months were not protected against emphysema. Mice exposed to smoke showed increases in gene expression of neutrophil chemoattractant macrophage inflammatory protein-2, macrophage chemoattractant protein-1, and TNF-{alpha} at 2 hours along with increased plasma TNF-{alpha}; ZD0892 prevented the increases in macrophage inflammatory protein-2 and macrophage chemoattractant protein-1 expression and reduced plasma TNF-{alpha} levels to baseline. These data demonstrate that a serine elastase inhibitor ameliorates the inflammatory and destructive effects of cigarette smoke, and that these effects are mediated in part by neutrophils and by smoke-driven TNF-{alpha} production.

Key Words: {alpha}1-antiprotease • neutrophil elastase • proteolysis • proteases




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