Matrix Metalloproteinase Expression and Production by Alveolar Macrophages in Emphysema

Abstract

The aim of this study was to examine the hypothesis that alveolar macrophages represent a significant source of matrix-degrading proteinases in the emphysematous lung. Macrophages from bronchoalveolar lavage fluid of 10 patients with emphysema and 10 normal volunteers were maintained in vitro for 24 h and assessed semiquantitatively for mRNA transcript levels of the matrix metalloproteinases (MMPs) gelatinases A and B, macrophage metalloelastase (MME), and interstitial collagenase. Release of these MMPs into the culture medium and secretion of neutrophil elastaselike activity was also assessed. Elevated levels of mRNA transcripts for gelatinase B (p < 0.0005) and interstitial collagenase (p < 0.0005) were observed in macrophages from emphysematous patients. Increased collagenase (p < 0.01) and neutrophil elastaselike activities (p < 0.001) were also measured in conditioned medium from patient macrophages. With gelatinase B, complexed forms of the enzyme were secreted by patient but not by control macrophages. No difference in transcript levels of gelatinase A or MME was observed between patient and control samples, and neither enzyme was detected in macrophage-conditioned media from either group. These results directly demonstrate that alveolar macrophages from the emphysematous lung produce elevated quantities of matrix-degrading enzymes with both elastolytic and collagenolytic activities.

Chemokine receptor CXCR3 is important for lung tissue damage and airway remodeling induced by short-term exposure to cigarette smoking in mice

“…In this study, our data demonstrate that over-activation of TGFβ1 together with MMP2 and MMP12 expression at the mRNA level in WT mice, which is partly in accordance with the previous reports that increased MMPs at the protein level were seen in patients with emphysema [27,28] , have tissue destructive and fibrotic effects depending on the location (either in parenchyma or in airways) [31] . It should be pointed out that the current study was based on a short-term exposure model.…”

“…Elias and colleagues have provided evidence that these enzymes may be regulated by proximal immune events through a Th1 cell-or IFNγ-dependent manner [26] . T cells, particularly CD8+ T cells, accumulate in the lungs of patients with COPD and generate signals such as CXCL10/ IP-10 that promote MMP12 production by macro phages [27,28] . Moreover, CXCR3 expressed by human T cells and macrophages is required for MMP12 secretion in response to IP-10/Mig stimulation [24] .…”

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: Potential implications in asthma and other lung diseases

“…In bronchoalveolar lavage fluid of smokers with emphysema, an increase of collagenolytic activity, probably due to elevated levels of MMP-8, is measured when compared to smokers without emphysema (Betsuyaku et al, 1999) indicating that injury to the collagen network of the lung is also a part of the disease. When studied ex vivo, alveolar macrophages from patients with emphysema express more MMP-1 and MMP-9 than macrophages from healthy subjects suggesting that macrophages are the main cellular source of MMP-1 and MMP-9 in COPD (Finlay et al, 1997a). As it has a potent elastolytic activity, MMP-12 is thought to play a determinant role in development of COPD and emphysema.…”

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

“…Transgenic mice expressing human collagenase (MMP-1) develop emphysematous changes in their lungs (10) caused by months of proteolytic damage to the lung parenchyma (15). Human studies reveal increased collagenolytic activity in bronchoalveolar lavage fluid and lung tissue from patients with chronic obstructive pulmonary disease (8,16,17). In addition, a recent report identified MMP-1 mRNA and protein in lung samples from human emphysema patients but not in lung samples from healthy subjects (9).…”