Transgenic expression of matrix metalloproteinase-9 causes adult-onset emphysema in mice associated with the loss of alveolar elastin

Abstract

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 ϭ 50 Ϯ 3 littermate mice vs. 51 Ϯ 2 transgenic mice). However, after 12 mo of age, the MMP-9 transgenic mice developed significant air space enlargement (mean linear intercept ϭ 53 Ϯ 3 littermate mice vs. 61 Ϯ 2 MMP-9 transgenic mice; P Ͻ 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 Ϯ 0.3% area of alveolar wall in the littermate mice vs. 3.3 Ϯ 0.3% area of alveolar wall in the MMP-9 mice; P Ͻ 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.protease; extracellular matrix; degradation; macrophage SEVERAL STUDIES HAVE IMPLICATED matrix metalloproteinase (MMP)-9 in the pathogenesis of emphysema. Increased MMP-9 levels were detected in emphysema lung samples (36), and enhanced expression of this protease was noted in alveolar macrophages from chronic obstructive pulmonary disease (COPD) patients (11,43). Similarly, elevated MMP-9 expression and activity were identified in animal models of the disease (58, 68) and were thought to play a role in the destructive process. While these studies associate MMP-9 activity with emphysema, they do not establish that MMP-9 is directly capable of generating structural changes in this disease. Indeed, MMP-9 could be functioning primarily to mediate postinjury repair response in the lungs of COPD patients (29,30). Alveolar macrophages are a major site of production of matrix-degrading enzymes in the lung (11), and these cells exert a key role on the alveolar destruction that occurs in this disease (65,66). Macrophages secrete several proteases that have been implicated in emphysema formation, including the elastolytic cysteine proteinases (cathepsin L and cathepsin S) and several MMPs (MMP-1, -9, and -12; Ref. 49). MMP-9, however, is the protease that has been most consistently identified from the alveolar macrophages of COPD patients (32, 44). Macrophages from COPD patients have increased MMP-9 expression (12) and release greater amounts of MMP-9 upon stimulation with cigarette smoke compared with macrophages from smoking and nonsmoking control subjects (43). These findings are relevant, as MMP-9 is capable of degrading key components of the extracellular matrix (24). Thus its exp...

Soluble CD200 Correlates With Interleukin-6 Levels in Sera of COPD Patients: Potential Implication of the CD200/CD200R Axis in the Disease Course

“…However, only nominal concentrations of these cytokines were detectable and no differences between the CD200KO and wild-type mice were observed (data not shown). Since MMPs are crucially involved in the development of emphysematous lesion in COPD, we also analyzed the levels of MMP-9, one of the lead MMPs in emphysema formation [27]. Indeed, we observed significantly increased concentrations of MMP-9 in 4 weeks elastase/LPS exposed CD200KO mice compared to wild-type control animals (Fig 4).…”

Targeted Disruption of Ig-Hepta/Gpr116 Causes Emphysema-like Symptoms That Are Associated with Alveolar Macrophage Activation

“…MMP-2 and MMP-9 are known to degrade type IV collagen and gelatin, which are major components of the extracellular matrix (53)(54)(55). Their excess activity has been thought to contribute to the development of emphysema through extensive destruction of the extracellular matrix and remodeling of lung parenchyma (54,56,57). Therefore, we propose that the alveolar enlargement in Ig-Hepta Ϫ/Ϫ may result from the overactivation of the MMPs, which causes alveolar tissue destruction and remodeling.…”

Second hand smoke and COPD: lessons from animal studies

“…Other laboratories have built upon the MMP-12 work, documenting the importance of additional MMPs in emphysema pathogenesis (Shapiro et al, 2003;Seagrave et al, 2004;March et al, 2006;Valenca et al, 2006;Foronjy et al, 2008;Vecchio et al, 2010). Our laboratory has demonstrated that the transgenic overexpression of MMP-9 in macrophages causes spontaneous adult-onset emphysema due to elastin degradation (Foronjy et al, 2008).…”

“…Our laboratory has demonstrated that the transgenic overexpression of MMP-9 in macrophages causes spontaneous adult-onset emphysema due to elastin degradation (Foronjy et al, 2008). In contrast, Atkinson and colleagues have shown that the MMP-9 deficient mouse still develops smoke-induced emphysema (Atkinson et al, 2011).…”