Release and Activity of Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 by Alveolar Macrophages from Patients with Chronic Obstructive Pulmonary Disease

Abstract

Destruction of lung elastin is critical for development of emphysema associated with chronic obstructive pulmonary disease (COPD). Lung macrophages release elastolytic enzymes, including matrix metalloproteinase (MMP)-9, along with tissue inhibitors of MMP (TIMP). We examined the production and activity of macrophage-derived MMP-9 and TIMP-1 from alveolar macrophages (AM) from smokers with COPD, healthy smokers (HS), and nonsmokers (NS). AM were stimulated with either lipopolysaccharide (LPS), interleukin (IL)-1 beta, or cigarette smoke-conditioned culture medium (CSM). AM from patients with COPD released greater amounts of MMP-9 with greater enzymatic activity than HS and NS. In contrast, AM from NS released more TIMP-1 than cells from HS and subjects with COPD. LPS and IL-1 beta caused a dose-dependent increase in MMP-9 release and activity, together with increased levels of TIMP-1. Dexamethasone prevented the increase in MMP-9 release, and increased TIMP-1 release. CSM increased MMP-9 and TIMP-1 release from AM of all groups. Dexamethasone decreased CSM-stimulated MMP-9 release, but had no effect on MMP-9 activity This study suggests that macrophages might be important in the development of COPD because these cells exhibit increased levels of elastolytic activity.

Pulmonary vascular changes in asthma and COPD

“…These neutrophils respond stronger to chemotactic factors and attach easier to the endothelial cell layer, which may promote ongoing inflammation and emphysema formation in the lung [99]. In patients with COPD there are an increased number of macrophages in the airways, lung parenchyma and BALf and the numbers of macrophages correlates well with the different GOLD stages of COPD [100].…”

Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis

“…MMP-2, MMP-9, and MMP-12 have been implicated in this ECM-destructive disease (30 -32). Both MMP-2 and MMP-9 are capable of elastolysis as well as collagenolysis (33), while MMP-12 is elevated in mice exposed to cigarette smoke and MMP-12 KO mice are protected from cigarette smoke-induced emphysema (30), and alveolar macrophages release more MMP-9 in chronic obstructive pulmonary disease patients and cigarette smokers (34,35). Osteopetrotic mice, deficient in macrophage CSF, develop emphysema and have higher levels of MMP-2, MMP-9, and MMP-12 in BAL fluid and alveolar macrophages than in controls (36), while lung surfactant protein D gene-inactivated mice have airspace enlargement associated with an increase in the same three MMPs (37).…”

Phenotypic characterisation of alveolar macrophages and peripheral blood monocytes in COPD

“…In patients with COPD, AM release more matrix metalloproteinase-9 [13] and interleukin-8 [14], and less tissue inhibitor of metalloproteinase-1 [13,15] and transforming growth factor-b 1 [15] than healthy smokers, and also have a limited ability to phagocytose apoptotic cells [16]. Yet, to date their surface phenotype has not been characterised although several previous studies have investigated the influence of tobacco smoking upon AM surface phenotype [17][18][19][20][21][22][23][24].…”