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Tissue Factor Expression in Neutrphils : Its Expression Mechanism and Pathogenesis

中性粒细胞中组织因子的表达：表达机制及发病机制

基本信息

批准号：
12670984
负责人：
NAKAMURA Shin
金额：
$ 2.24万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670984/
关键词：
Tissue Factor Neutrophil Thrombosis Arteriosclerosis Inflammation Infection Coagulation Leukocyte Activation

项目摘要

TF is a 47 kDa transmembrane glycoprotein that plays an essential role in the initiation of the extrinsic coagulation protease cascade. It functions as a high-affinity receptor and co factor for plasma factors VII (FVII) and VIIa (2,3). The formation of a complex between factor VIIa and TF initiates the proteolytic activation of factors IX and X, leading to the generation of thrombin and the conversion of fibrinogen into fibrin. TF is selectively expressed in tissues and is normally not present within the vasculature. However, two cell types within the vasculature, monocyte and endothelial cell , can be induced to express TF by a variety of stimuli in vitro. LPS), thrombin , the occupancy of cell adhesion molecules (selectins and integrins), and inflammatory cytokines (14) such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) are among the known inducers of these cell TF expressions in vitro.The aberrant expression of TF is implicated in the pathogenesis of disorders such as Gra … More m-negative septicemia, thromboembolism, and several forms of DIC (15). The involvement of TF in septic DIC is supported by the demonstration that TF neutralizing antibodies prevent the evolution of DIC and the lethal effects of bacterial infusion in a baboon model (16). However, while the in vivo expression of TF in monocyte has been clearly demonstrated, whether endothelial cell can express TF in vivo remains controversial.We recently demonstrated that neutrophils as well as monocytes express tissue factor (TF) in a rabbit model of acute obstructive cholangitis. However, rabbit neutrophil is different from primate neutrophil in a strict sense. To clarify the ability of neutrophils to express TF, we investigated the expression of TF mRNA and the protein in the lipopolysaccharide (LPS) administrated monkey model. We found that TF mRNA was induced in neutrophils as well as monocytes and endothelial cells accumulated in the liver 3 h after the LPS injection. Electron microscopic immunohistochemistry revealed that TF protein was positive in the rough endoplasmic reticulum and plasma membrane in the neutrophils. The fibrin was formed on neutrophils. The plasma levels of fibrin degradation products-D dimer (D-dimer) were significantly increased at 1.5 h compared to pre-administration state. These results suggest that TF expression in neutrophils, previous unknown mechanism, may promote DIC during sepsis. Less

Tf是一种大小为47 kDa的跨膜糖蛋白，在启动外源性凝血酶的级联反应中起重要作用。它作为血浆因子VII(FVII)和VIIa(2，3)的高亲和力受体和辅助因子发挥作用。凝血因子VIIa和转铁蛋白之间的复合体启动了第IX和第X因子的蛋白水解性激活，导致凝血酶的产生和纤维蛋白原向纤维蛋白的转化。转铁蛋白在组织中有选择性地表达，通常不存在于血管内。然而，血管系统中的两种细胞类型，单核细胞和内皮细胞，在体外可以被各种刺激诱导表达TF。Tf的异常表达与Gra-…等疾病的发病机制有关更多的m阴性败血症、血栓栓塞症和几种形式的DIC(15)。转铁蛋白在感染性DIC中的参与得到了以下证明的支持：转铁蛋白中和抗体可防止DIC的演变以及在狒狒模型中细菌输注的致死作用。然而，尽管在单核细胞中表达组织因子已被明确证明，但内皮细胞是否在体内表达组织因子仍存在争议。我们最近在兔急性梗阻性胆管炎模型中证明了中性粒细胞和单核细胞都表达组织因子(TF)。然而，兔中性粒细胞在严格意义上不同于灵长类中性粒细胞。为了阐明中性粒细胞表达转铁蛋白的能力，我们观察了脂多糖(LPS)诱导的猕猴模型中性粒细胞表达转铁蛋白的情况。结果发现，注射内毒素后3h，肝脏中性粒细胞、单核细胞和内皮细胞均有Tf基因表达。电镜免疫组织化学显示，中性粒细胞的粗面内质网和质膜中均有TF蛋白阳性表达。纤维蛋白形成于中性粒细胞上。血浆纤维蛋白降解产物D-二聚体(D-二聚体)水平在给药后1.5h较给药前显著升高。这些结果表明，中性粒细胞中TF的表达可能促进脓毒症时的DIC，其机制尚不清楚。较少