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Published ahead of print on March 29, 2007, doi:10.1165/rcmb.2006-0345OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 2, August 2007, 144-151

A more recent version of this article appeared on August 1, 2007
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Submitted on September 11, 2006
Revised on March 29, 2007

{alpha}-1-Antitrypsin Suppresses TNF{alpha} and MMP-12 Production by Cigarette Smoke-Stimulated Macrophages

Andrew Churg1*, Xiaoshan Wang1, Rong D Wang1, Scott C Meixner2, Edward LG Pryzdial2, and Joanne L Wright1

1 Department of Pathology, University of British Columbia, Vancouver, BC, Canada, 2 Department of Pathology, University of British Columbia, Vancouver, BC, Canada; Canadian Blood Services, Research and Development Department, Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada

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

We have previously observed that mice exposed to cigarette smoke and treated with exogenous {alpha}-1-antitrypsin (A1AT) were protected against the development of emphysema and against smoke-induced increases in serum TNF{alpha}. To investigate possible mechanisms behind this latter observation, we cultured alveolar macrophages lavaged from C57 mice. Smoke-conditioned medium caused alveolar macrophages to increase secretion of MMP-12 and TNF{alpha}, and this effect was suppressed in a dose-response fashion by addition of A1AT. Macrophages from animals exposed to smoke in vivo and then lavaged also failed to increase MMP-12 and TNF{alpha} secretion when the animals were pretreated with A1AT. Because proteinase activated receptor-1 (PAR-1) is known to control MMP-12 release, macrophages were treated with the G protein coupled receptor inhibitor, pertussis toxin; this suppressed both TNF{alpha} and MMP-12 release, while a PAR-1 agonist (TRAP) increased TNF{alpha} and MMP-12 release. Smoke-conditioned medium caused increased release of the prothrombin activator, tissue factor, from macrophages. Hirudin, a thrombin inhibitor, and aprotinin, an inhibitor of plasmin, reduced smoke-mediated TNF{alpha} and MMP-12 release, and A1AT inhibited both plasmin and thrombin activity in a cell-free functional assay. These findings extend our previous suggestion that TNF{alpha} production by alveolar macrophages is related to MMP-12 secretion. They also suggest that A1AT can inhibit thrombin and plasmin in blood constituents that leak into the lung after smoke exposure, thereby preventing PAR-1 activation and MMP-12/TNF{alpha} release, and decreasing smoke-mediated inflammatory cell influx.




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