Tissue Factor Expression in Neutrphils : Its Expression Mechanism and Pathogenesis

TF是一个47 kDa的跨膜糖蛋白，在外源性凝血蛋白酶级联的启动中起重要作用。它是血浆因子VII （FVII）和VIIa的高亲和力受体和辅助因子（2,3）。因子VIIa和TF之间形成复合物，启动因子IX和因子X的蛋白水解激活，导致凝血酶的生成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，血管内的两种细胞类型，单核细胞和内皮细胞，可以通过各种体外刺激诱导表达TF。脂多糖（LPS）、凝血酶、细胞粘附分子（选择素和整合素）的占据以及炎症因子（14），如白细胞介素-1 （IL-1）和肿瘤坏死因子（TNF），都是这些细胞TF在体外表达的已知诱导剂。TF的异常表达与Gra…More m阴性败血症、血栓栓塞和几种DIC等疾病的发病机制有关（15）。在狒狒模型中，TF中和抗体可阻止DIC的进化和细菌输注的致死效应，这证实了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得到明确证实，但内皮细胞是否能在体内表达TF仍存在争议。我们最近证明了中性粒细胞和单核细胞在兔急性梗阻性胆管炎模型中表达组织因子（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TF的能力，我们在脂多糖（LPS）给药的猴子模型中研究了TF mRNA和蛋白的表达。我们发现，在LPS注射后3小时，肝脏中积累的中性粒细胞、单核细胞和内皮细胞中诱导了TF mRNA。电镜免疫组化显示TF蛋白在中性粒细胞粗内质网和质膜中呈阳性。纤维蛋白在中性粒细胞上形成。与给药前相比，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，中性粒细胞中TF的表达可能促进脓毒症期间DIC的发生，其机制尚不清楚。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