title: Transgenic expression of matrix metalloproteinase-9 causes adult-onset emphysema in mice associated with the loss of alveolar elastin.
abstract: Matrix metalloproteinase (MMP)-9 has been consistently identified in the lungs of patients with chronic obstructive pulmonary disease (COPD). However, its role in the development of the disease remains undefined. Mice that specifically express human MMP-9 in their macrophages were generated, and morphometric, biochemical, and histological analyses were conducted on the transgenic and littermate control mice over 1 yr to determine the effect of macrophage MMP-9 expression on emphysema formation and lung matrix content. Lung morphometry was normal in transgenic mice at 2 mo of age (mean linear intercept = 50+/-3 littermate mice vs. 51+/-2 transgenic mice). However, after 12 mo of age, the MMP-9 transgenic mice developed significant air space enlargement (mean linear intercept = 53+/-3 littermate mice vs. 61+/-2 MMP-9 transgenic mice; P<0.04). Lung hydroxyproline content was not significantly different between wild-type and transgenic mice, but MMP-9 did significantly decrease alveolar wall elastin at 1 yr of age (4.9+/-0.3% area of alveolar wall in the littermate mice vs. 3.3+/-0.3% area of alveolar wall in the MMP-9 mice; P<0.004). Thus these results establish a central role for MMP-9 in the pathogenesis of this disease by demonstrating that expression of this protease in macrophages can alter the extracellular matrix and induce progressive air space enlargement in mice.
authors.affiliation: Columbia University, New York, New York, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Foronjy
authors.forename: Takwi
authors.initials: T
authors.lastname: Nkyimbeng
authors.forename: Alison
authors.initials: A
authors.lastname: Wallace
authors.forename: Jincy
authors.initials: J
authors.lastname: Thankachen
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.forename: Vincent
authors.initials: V
authors.lastname: Lemaitre
authors.forename: Jeanine
authors.initials: J
authors.lastname: D'Armiento
mesh_terms: D000818:Animals; D004549:Elastin / Q000378:metabolism*; D004646:Emphysema / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008168:Lung / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology
chemical_list: D004549:Elastin; D020780:Matrix Metalloproteinase 9