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₁-Antitrypsin Suppresses TNF- and MMP-12 Production by Cigarette Smoke–Stimulated Macrophages

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

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, V6T 2B5 Canada. E-mail: achurg{at}interchange.ubc.ca

We have previously observed that mice exposed to cigarette smoke and treated with exogenous ₁-antitrypsin (A1AT) were protected against the development of emphysema and against smoke-induced increases in serum TNF-. 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 macrophage metalloelastase (MMP-12) and TNF-, 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- 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- and MMP-12 release, while a PAR-1 agonist (TRAP) increased TNF- 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- 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- 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- release, and decreasing smoke-mediated inflammatory cell influx.

Key Words: cigarette smoke • emphysema • ₁-antitrypsin • MMP-12 • thrombin

CLINICAL RELEVANCE This article shows that 1-antitrypsin can suppress cigarette smoke–induced production of TNF- and MMP-12 by alveolar macrophages, a novel mechanism that will lead to suppression of TNF-–mediated inflammation and thus prevent emphysema.

 

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