Alpha1-antitrypsin suppresses TNF-alpha and MMP-12 production by cigarette smoke-stimulated macrophages

Am J Respir Cell Mol Biol. 2007 Aug;37(2):144-51. doi: 10.1165/rcmb.2006-0345OC. Epub 2007 Mar 29.


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 macrophage metalloelastase (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Culture Media, Conditioned
  • Dose-Response Relationship, Drug
  • Fibrinolysin / metabolism
  • Fibrinolytic Agents / metabolism
  • Hirudins / metabolism
  • Humans
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / metabolism*
  • Matrix Metalloproteinase 12 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Pertussis Toxin / metabolism
  • Smoke
  • Smoking / adverse effects
  • Thrombin / metabolism
  • Tobacco / adverse effects
  • Tumor Necrosis Factor-alpha / metabolism*
  • alpha 1-Antitrypsin / metabolism*
  • alpha 1-Antitrypsin / pharmacology


  • Culture Media, Conditioned
  • Fibrinolytic Agents
  • Hirudins
  • Smoke
  • Tumor Necrosis Factor-alpha
  • alpha 1-Antitrypsin
  • Pertussis Toxin
  • Thrombin
  • Fibrinolysin
  • Matrix Metalloproteinase 12