title: Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-alpha release.
abstract: 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 MMP-12 (MMP-12 -/-) demonstrated rapid increases in whole-lung nuclear factor-kappaB activation and gene expression of proinflammatory cytokines after cigarette smoke exposure, indicating that a 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 (TNF-alpha) protein or release of TNF-alpha from cultured alveolar macrophages exposed to smoke in vitro. Levels of whole-lung E-selectin, an endothelial activation marker, were increased in only MMP-12 +/+ mice. These findings suggest that, acutely, MMP-12 mediates smoke-induced inflammation by releasing TNF-alpha from macrophages, with subsequent endothelial activation, neutrophil influx, and proteolytic matrix breakdown caused by neutrophil-derived proteases. TNF-alpha release may be a general mechanism whereby metalloproteases drive cigarette smoke-induced inflammation.
authors.affiliation: Department of Pathology, University of British Columbia, Vancouver, Canada. achurg@interchange.ubc.ca
authors.forename: Andrew
authors.initials: A
authors.lastname: Churg
authors.forename: Rong D
authors.initials: RD
authors.lastname: Wang
authors.forename: Hsin
authors.initials: H
authors.lastname: Tai
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Wang
authors.forename: Changshi
authors.initials: C
authors.lastname: Xie
authors.forename: Jin
authors.initials: J
authors.lastname: Dai
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Wright
mesh_terms: D000208:Acute Disease; D000818:Animals; D002478:Cells, Cultured; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000276:immunology*; D051379:Mice; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology*; D012907:Smoking / Q000009:adverse effects* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12