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Published ahead of print on January 9, 2003, doi:10.1164/rccm.200212-1396OC
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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1083-1089, (2003)
© 2003 American Thoracic Society

Original Article

Macrophage Metalloelastase Mediates Acute Cigarette Smoke–induced Inflammation via Tumor Necrosis Factor-{alpha} Release

Andrew Churg, Rong D. Wang, Hsin Tai, Xiaoshan Wang, Changshi Xie, Jin Dai, Steven D. Shapiro and Joanne L. Wright

Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada; and Division of Respiratory Medicine, Brigham and Women's Hospital, Boston, Massachusetts

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

The cells and proteases that mediate cigarette smoke–induced emphysema are controversial, with evidence favoring either neutrophils and neutrophil-derived serine proteases or macrophages and macrophage-derived metalloproteases as the important effectors. We recently reported that both macrophage metalloelastase (MMP-12) and neutrophils are required for acute cigarette smoke-induced connective tissue breakdown, the precursor of emphysema. Here we show how these disparate observations can be linked. Both wild-type (MMP-12 +/+) mice and mice lacking MMP-12 (MMP-12 -/-) demonstrated rapid increases in whole-lung nuclear factor-{kappa}B activation and gene expression of proinflammatory cytokines after cigarette smoke exposure, indicating that a lack of MMP-12 does not produce a global failure to upregulate inflammatory mediators. However, only MMP-12 +/+ mice demonstrated increased whole-lung tumor necrosis factor-{alpha} (TNF-{alpha}) protein or release of TNF-{alpha} from cultured alveolar macrophages exposed to smoke in vitro. Levels of whole-lung E-selectin, an endothelial activation marker, were increased in only MMP-12 +/+ mice. These findings suggest that, acutely, MMP-12 mediates smoke-induced inflammation by releasing TNF-{alpha} from macrophages, with subsequent endothelial activation, neutrophil influx, and proteolytic matrix breakdown caused by neutrophil-derived proteases. TNF-{alpha} release may be a general mechanism whereby metalloproteases drive cigarette smoke–induced inflammation.

Key Words: chronic obstructive pulmonary disease • tumor necrosis factor-{alpha} • cigarette smoke • macrophage metalloelastase • neutrophils • metalloproteases




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