In the blood coagulation cascade, human antithrombin III (hAT III) acts as an inhibitor of serine proteases such as thrombin and factor Xa, and this anticoagulatory glycoprotein requires the binding of heparin for its activation. In this study, we synthesized the polypeptides corresponding to the proposed heparin-binding sites including the (41-49), (286-301) and (123-139) regions of hAT III, and examined their interactions with heparin by means of physicochemical and biochemical methods. All the synthetic peptides had a high affinity toward heparin, evidenced by the fact that they were eluted from a heparin-agarose column at the high salt concentration range of 520-700 mM. In addition, hAT III (123-139) attenuated the effect of heparin on the activation of hAT III, whereas other HBPs did not, suggesting that only hAT III (123-139) could interact with the active site of heparin. On the basis of these results, we prepared novel hAT III (123-139)-related derivatives as potent heparin antagonist candidates, and examined the influence of several modifications on their activity in vitro. The results provided new findings about the structure-activity relationship of hAT III (123-139), and led us to the successful development of a potent antagonist for heparin.

1990-08-01·Journal of Cell Science2区 · 生物学

Promotion of transendothelial neutrophil passage by human thrombin

2区 · 生物学

Article

作者: Moser, René ; Fehr, Jorg ; Groscurth, Peter

ABSTRACTThrombin has been reported to elicit two temporally different effects on neutrophil-endothelial interaction, categorically described as ‘neutrophil adhesion’: one expressed within a few minutes, the other after several hours of endothelial preincubation. Prolonged activation resulted in often elongated, tightly interacting neutrophils in contact with human umbilical vein endothelial cells (HUVE) mainly at the intercellular region. In contrast, the neutrophil-endothelial interaction due to short-time priming with thrombin was dominated by round, randomly distributed neutrophils, loosely adhering on the endothelial surface. Sheer stress, introduced to characterize these morphological entities in a quantitative manner, clearly defined the neutrophil response due to short time priming as sheer stresslabile compared to the sheer stress-resistant interaction expressed after prolonged preincubation of HUVE with thrombin. Quantitative determination of neutrophil transendothelial migration served to demonstrate the relevance of such differences in neutrophil binding with respect to subsequent layer penetration. Dependent upon endothelial protein synthesis and inhibited by antithrombin-III-heparin and hirudin, neutrophil layer penetration only occurred after prolonged activation of HUVE whereas the neutrophil-endothelial interaction due to short time priming with thrombin was limited to superficial neutrophil adhesion.We conclude that thrombin can be added to the list of activators capable of inducing the neutrophil passage-guiding principle, an effect that has recently been detected as closely related to neutrophil adhesion to endothelial ligands expressed upon activation with interleukin-1 and tumor necrosis factor. This biological activity, which can be separated from superficial attachment of polymorphonuclear leukocytes (PMN) to endothelial cells, is a catalytic sitedependent and late phase-specific effect of thrombin on HUVE.

1987-10-01·European Journal of Obstetrics & Gynecology and Reproductive Biology4区 · 医学

Demonstration of the ability of Hofbauer cells to phagocytose exogenous antibodies

4区 · 医学

Article

作者: Hans Ludwig ; Martine Frauli

We have studied the effects of the anti-human chorionic gonadotropin and anti-human antithrombin III antibodies on Hofbauer cells from human immature placenta, when applied to either intact villi or on cell culture. Trypsin treatment of the villi results in a mixed cell culture mainly composed of isolated Hofbauer cells but which also contains a variable number of mesenchymal cells and a few syncytiotrophoblastic cells. In all samples analysed only 7-8% of the Hofbauer cells and some syncytiotrophoblastic cells exhibited a macrophagic activity 24 h after incubation of the cultures with the antisera. That only certain proportions of Hofbauer and syncytiotrophoblastic cells express macrophagic activity is also seen when intact villi are incubated for 24 h with these antibodies. Indeed, neither all the villi nor all these cells within a single villus are positively stained. The fact that only a fraction of Hofbauer cells and syncytiotrophoblast express a macrophagic activity may suggest that only some cells, amongst both these cell types, are involved in the protection of the fetus against maternal immunological rejection by removing immunological complexes.

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适应症	最高研发状态	国家/地区	公司	日期
肝移植排斥反应	临床2期	韩国	Seoul National University Hospital	2020-01-03
肝静脉闭塞性疾病	临床2期	-	Seoul National University Hospital	-