Neutrophil elastase in human atherosclerotic plaques - Production by macrophages
Neutrophil elastase in human atherosclerotic plaques - Production by macrophages
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DOI：
10.1161/01.cir.0000072792.65250.4a
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发表时间：
2003-06-10
期刊：
影响因子：
37.8
通讯作者：
Libby, P
中科院分区：
文献类型：
--
作者：
Dollery, CM;Owen, CA;Libby, P
背景-细胞外基质（ECM）的分解代谢有助于健康和疾病中的血管重塑。尽管金属酶和半胱氨酸蛋白酶在这方面引起了广泛关注，但丝氨酸依赖性蛋白酶在动脉粥样硬化形成过程中血管 ECM 降解中的作用仍不清楚。我们最近发现在动脉粥样硬化相关细胞中存在金属蛋白酶 MMP-8，传统上仅与中性粒细胞相关。人中性粒细胞弹性蛋白酶（NE）在肺部疾病中发挥着关键作用，但动脉粥样硬化斑块中中性粒细胞的缺乏导致人们忽视了它在血管生物学中的潜在作用。 NE 除了具有修饰脂蛋白和调节细胞因子和 MMP 活性的能力外，还可以消化弹性蛋白、纤维状和非纤维状胶原蛋白以及其他 ECM 成分。方法和结果-纤维状和粥样斑块但不含有 NE 的正常动脉。特别是，NE在具有脆弱组织学特征的粥样斑块富含巨噬细胞的肩部中大量存在。中性粒细胞弹性蛋白酶和巨噬细胞共定位于此类易损斑块中 (n = 7)。原位杂交揭示了巨噬细胞丰富区域的 NE mRNA，表明这种酶的本地产生。新鲜分离的血液单核细胞、单核细胞来源的巨噬细胞和培养的血管内皮细胞产生活性 NE 并含有 NE mRNA。单核细胞组成性地产生 NE，几乎不受细胞因子 IL-1beta、TNF-α 或 IFN-gamma 的调节，但在受到 CD40 配体（动脉粥样硬化中发现的一种细胞因子）刺激时会释放 NE。结论 - 这些发现表明丝氨酸蛋白酶、中性粒细胞弹性蛋白酶在巨噬细胞的基质分解中具有新作用，巨噬细胞是血管适应性重塑和动脉疾病发病机制的关键过程。
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.