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Published ahead of print on January 9, 2003, doi:10.1164/rccm.200212-1396OC

Am. J. Respir. Crit. Care Med., Volume 167, Number 8, April 2003, 1083-1089

A more recent version of this article appeared on April 15, 2003
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Submitted on December 1, 2002
Accepted on January 8, 2003

Macrophage Metalloelastase Mediates Acute Cigarette Smoke-Induced Inflammation Via TNF-alpha Release

Andrew Churg1*, Rong D Wang1, Hsin Tai1, Xiaoshan Wang1, Changshi Xie1, Jin Dai1, Steven D Shapiro2, and Joanne L Wright1

1 Department of Pathology, University of British Columbia, Vancouver, BC, Canada, 2 Respiratory Medicine, Brigham and Women's Hospital, Boston, MA, USA

* To whom correspondence should be addressed. 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 macrophage metalloelastase (MMP-12 -/-) demonstrated rapid increases in whole lung nuclear factor-{kappa}B activation and gene expression of pro-inflammatory cytokines after cigarette smoke exposure, indicating that 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} protein or release of tumor necrosis factor-{alpha} from cultured alveolar macrophages exposed to smoke in vitro. Levels of whole lung e-selectin, an endothelial activation marker, were only increased in MMP-12 +/+ mice. These findings suggest that, acutely, MMP-12 mediates smoke-induced inflammation by releasing tumor necrosis factor-{alpha} from macrophages, with subsequent endothelial activation, neutrophil influx, and proteolytic matrix breakdown caused by neutrophil-derived proteases. Tumor necrosis factor-{alpha} release may be a general mechanism whereby metalloproteases drive cigarette smoke-induced inflammation.
Key words: COPD,TNF-alpha, cigarette smoke, MMP-12, neutrophils,




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