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Neutrophil elastase in human atherosclerotic plaques: production by macrophages

Dollery, CM; Owen, CA; Sukhova, GK; Krettek, A; Shapiro, SD; Libby, P; (2003) Neutrophil elastase in human atherosclerotic plaques: production by macrophages. Circulation , 107 (22) pp. 2829-2836.

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BACKGROUND: Catabolism of the extracellular matrix (ECM) contributes to vascular remodeling in health and disease. Although metalloenzymes and cysteinyl proteinases have garnered much attention in this regard, the role of serine-dependent proteinases in vascular ECM degradation during atherogenesis remains unknown. We recently discovered the presence of the metalloproteinase MMP-8, traditionally associated only with neutrophils, in atheroma-related cells. Human neutrophil elastase (NE) plays a critical role in lung disease, but the paucity of neutrophils in the atheromatous plaque has led to neglect of its potential role in vascular biology. NE can digest elastin, fibrillar and nonfibrillar collagens, and other ECM components in addition to its ability to modify lipoproteins and modulate cytokine and MMP activity. METHODS AND RESULTS: Fibrous and atheromatous plaques but not normal arteries contained NE. In particular, NE abounded in the macrophage-rich shoulders of atheromatous plaques with histological features of vulnerability. Neutrophil elastase and macrophages colocalized in such vulnerable plaques (n=7). In situ hybridization revealed NE mRNA in macrophage-rich areas, indicating local production of this enzyme. Freshly isolated blood monocytes, monocyte-derived macrophages, and vascular endothelial cells in culture produced active NE and contained NE mRNA. Monocytes produced NE constitutively, with little regulation by cytokines IL-1beta, TNF-alpha, or IFN-gamma but released it when stimulated by CD40 ligand, a cytokine found in atheroma. CONCLUSIONS: These findings point to a novel role for the serine protease, neutrophil elastase, in matrix breakdown by macrophages, a critical process in adaptive remodeling of vessels and in the pathogenesis of arterial diseases

Type: Article
Title: Neutrophil elastase in human atherosclerotic plaques: production by macrophages
Additional information: DA - 20030610 IS - 1524-4539 LA - eng PT - Journal Article RN - 0 (Antigens, CD) RN - 0 (Antigens, Differentiation, Myelomonocytic) RN - 0 (CD68 antigen, human) RN - 0 (Cytokines) RN - 0 (RNA, Messenger) RN - 147205-72-9 (CD40 Ligand) RN - EC (Leukocyte Elastase) SB - AIM SB - IM
Keywords: activity, Adaptive, ANTIGEN, Antigens, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Arterial, Arteries, Arteriosclerosis, artery, atheroma, Attention, biology, biosynthesis, Blood, Blotting, Western, Carotid Arteries, CATABOLISM, CD40, CD40 Ligand, cell, Cell Differentiation, CELLS, Cells, Cultured, Collagen, COMPONENT, COMPONENTS, culture, cytokine, Cytokines, cytology, degradation, differentiation, disease, Disease Progression, Diseases, drug effects, ECM, Elastin, Endothelial, endothelial cell, endothelial cells, ENDOTHELIAL-CELLS, Endothelium, Vascular, enzyme, enzymology, Extracellular Matrix, FEATURES, genetics, health, HYBRIDIZATION, IFN gamma, IFN-GAMMA, IM, Immunohistochemistry, in situ, in situ hybridization, LA, leukocyte, Leukocyte Elastase, LIGAND, lipoprotein, Lipoproteins, local, Lung, LUNG-DISEASE, macrophage, macrophages, MATRIX, metabolism, Metalloproteinase, Methods, Monocytes, mRNA, Muscle, Smooth, Vascular, neutrophil, neutrophils, novel, Other, PATHOGENESIS, pathology, pharmacology, Plaque, play, process, processes, Protease, regulation, Result, Rna, RNA, Messenger, Serine, SITU, Support, Non-U.S.Gov't, Support, U.S.Gov't, P.H.S., TNF ALPHA, TNF-ALPHA, Unknown, vascular, VASCULAR ENDOTHELIAL CELLS, vessels
URI: http://discovery.ucl.ac.uk/id/eprint/30088
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