| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Research Abstract |
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
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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
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