Tissue Factor Expression in Neutrphils : Its Expression Mechanism and Pathogenesis

TF是一种47 kDa的跨膜糖蛋白，在外源性凝血蛋白酶级联反应的启动中起重要作用。作为血浆因子VII（FVII）和VIIa的高亲和力受体和辅因子发挥作用（2，3）。因子VIIa和TF之间复合物的形成启动因子IX和X的蛋白水解活化，导致凝血酶的产生和纤维蛋白原转化为纤维蛋白。TF在组织中选择性表达，通常不存在于脉管系统中。然而，在血管系统中的两种类型的细胞，单核细胞和内皮细胞，可以被诱导表达TF在体外的各种刺激。LPS）、凝血酶、细胞粘附分子（选择素和整联蛋白）的占据以及炎性细胞因子（14）如白介素-1（IL-1）和肿瘤坏死因子（TNF）是这些细胞TF表达的体外已知诱导物。 ...更多信息 M阴性败血症、血栓栓塞和几种形式的DIC（15）。在狒狒模型中，TF中和抗体可预防DIC的发展和细菌输注的致死作用，这一证据支持TF参与脓毒性DIC（16）。然而，虽然TF在单核细胞中的体内表达已被清楚地证明，内皮细胞是否能在体内表达TF仍存在争议，我们最近证明，中性粒细胞以及单核细胞表达组织因子（TF）在兔急性梗阻性胆管炎模型。然而，兔中性粒细胞与灵长类中性粒细胞在严格意义上是不同的。为了阐明中性粒细胞表达TF的能力，我们研究了脂多糖（LPS）给药猴模型中TF mRNA和蛋白的表达。我们发现，TF mRNA的诱导中性粒细胞以及单核细胞和内皮细胞在肝脏中积累LPS注射后3小时。电镜免疫组化显示TF蛋白阳性表达于中性粒细胞的粗面内质网和质膜。中性粒细胞上形成纤维蛋白。与给药前状态相比，1.5 h时血浆纤维蛋白降解产物-D-二聚体（D-二聚体）水平显著升高。这些结果表明，TF在中性粒细胞的表达，以前未知的机制，可能会促进DIC在脓毒症。少

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