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Published ahead of print on June 7, 2004, doi:10.1164/rccm.200404-511OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 5, September 2004, 492-498

A more recent version of this article appeared on September 1, 2004
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Submitted on April 19, 2004
Accepted on June 7, 2004

Tumor Necrosis Factor-{alpha} Drives 70% of Cigarette Smoke-Induced Emphysema in the Mouse

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

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

* To whom correspondence should be addressed. E-mail: achurg{at}interchange.ubc.ca.

Mice lacking TNF{alpha} receptors (TNFRKO mice) do not develop an inflammatory infiltrate or matrix breakdown after a single acute cigarette smoke exposure. To determine the role of TNF{alpha} in the long-term development of emphysema, mice were exposed to smoke for 6 months. TNFRKO mice demonstrated an 11% increase in mean linear intercept; wild type mice had a 38% increase. TNFRKO mice had 65% fewer neutrophils and no increase in macrophages in lavage fluid. Whole lung MMP2,9, 12,13 and MT1-MMP protein was increased in wild type mice, but smaller increases in MMP12,MMP13, and MT1-MMP were also seen in TNFRKO mice. Lavage matrix breakdown products were elevated in wild type mice and only partially reduced by anti-neutrophil antibody, implying both neutrophil and non-neutrophil mediated matrix breakdown. We conclude that TNF{alpha}-mediated processes, probably driving PMN influx, are responsible for about 70% of airspace enlargement and the majority of inflammatory cell influx/matrix breakdown in the mouse model. TNF{alpha} causes increased MMP production, but some increased MMP activity is present even in TNFRKO mice. These findings imply a second, TNF{alpha}- independent, process, possibly related to direct MMP attack on matrix, that produces the remaining 30% of airspace enlargement.
Key words: Emphysema, TNF{alpha}, matrix metalloprotease, MMP12




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