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Elucidation of the mechanism of endotoxin-induced disseminated intravascular coagulation; Tissue factor activity in macrophage and granulocyte.

阐明内毒素诱导的弥散性血管内凝血的机制；

基本信息

批准号：
61570214
负责人：
HIRATA Michimasa
金额：
$ 1.54万
依托单位：
Iwate Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1986
资助国家：
日本
起止时间：
1986 至 1988
项目状态：
已结题

项目摘要

1. Tissue factor(TF). 1) By prior incubation of TF with fibronectin(FN), about 50 to 80 % of the TF activity was inhibited. 2) FN also inhibited the TF activity of bone marrow cells from mouse given endotoxin. 3) TF-induced lethality in mice was inhibited by preincubation of TF with FN. Inhibitory effect of FN on the TF activity is thought to be due to the binding of FN to phospholipid portion of TF. In Japanese monkey, 1) Endotoxin(LPS) induced a fever around 0.5 to 1.0 C that peaked at 1 hr. 2) LPS induced leukopenis 30 min after injection then followed by leukocytosis. 3) TF activities of monomuclear cell and granulocyte obtained from peripheral blood, spleen and bone marrow increased significantly compared to control 12 hr after LPS. 4) Plasma TNF(tumor necrosis factor) increased 0.5 to 1 hr after LPS to peak concentration of 250 to 390 pg/ml. 5) No increase in plasma IL-1 was observed during 12 hr. These indicate that TNF/cachectin released after LPS administration is thought to be a primary mediator responsible for initiation of these biological activities of LPS. 2. Cationic proteins(CAP). 1) CAP from rabbit granulocytes agglutinated sheep, human and mous erythrocvtes sensitized with LPS. (2) CAP prolonged the clotting time of human plasma. 3) Anticoagulant property rsulted from inhibition of factor Xa or prothrombinase formation. 4) CAP showed antibacterial activity to S. typhimurium, S. minnesota and also to S. aureus. 5) LPS-binding, anticoagulant and antibacterial activities were absorbed by prior incubation of CAP with LPS or heparin. 6) By gel filtration, two fractions had LOS-binding activities and the molecular weights were around 68K and 10K. These finding suggest that DIC( disseminated intravascular coagulation) manifestation in endotoxemia, due to gram negative bacterial infections, are controlled by CAP released from granulocytes.

1.组织因子(TF)。1)预先将TF与纤维连接蛋白(FN)孵育，可抑制约50%~80%的TF活性。2)FN还能抑制内毒素所致小鼠骨髓细胞的转铁蛋白活性。3)Tf与Fn预先孵育可抑制Tf诱导的小鼠致死率。FN对Tf活性的抑制作用可能是由于Fn与Tf的磷脂部分结合所致。在日本猴中，1)内毒素(LPS)引起约0.5-1.0摄氏度的发热，并在1小时达到高峰。2)注射后30min，内毒素引起白细胞减少，随后出现白细胞升高。3)外周血、脾和骨髓中单个核细胞和粒细胞的转铁蛋白活性在内毒素后12h显著高于对照组。4)血浆肿瘤坏死因子(肿瘤坏死因子)在内毒素后0.5~1h升高，峰值浓度为250~390pg/ml。提示脂多糖注射后释放的肿瘤坏死因子/cachectin被认为是启动脂多糖这些生物学活性的主要介质。2.阳离子蛋白(CAP)。1)兔粒细胞凝集绵羊、人和粘液致敏的红血球的CAP。(2)CAP可延长人血浆凝血时间。3)抑制凝血因子Xa或凝血酶原酶的形成所致的抗凝血性。4)CAP对鼠伤寒沙门氏菌、明尼苏达沙门氏菌和金黄色葡萄球菌均有抗菌活性。5)CAP与内毒素或肝素孵育后可吸收内毒素结合、抗凝血和抗菌作用。6)经凝胶过滤，两个组分均具有LOS结合活性，其相对分子质量分别在68K和10K左右。这些发现提示，革兰氏阴性细菌感染引起的内毒素血症的DIC(弥散性血管内凝血)表现受粒细胞释放的CAP控制。