一种靶向高分子量激肽原的抗体可在多微生物败血症模型中阻断接触系统激活。
An antibody targeting high-molecular-weight kininogen blocks contact system activation in a model of polymicrobial sepsis.
作者信息
Badimon Ana, Wu S Julia, Calvano Marissa, Strickland Sidney, Norris Erin H
机构信息
Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, New York, USA. Electronic address: https://twitter.com/ana_badimon.
Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, New York, USA; Division of Hematology/Oncology, New York Presbyterian-Weill Cornell Medical Center, New York, New York, USA.
出版信息
J Thromb Haemost. 2025 Aug 8. doi: 10.1016/j.jtha.2025.07.032.
BACKGROUND
Polymicrobial sepsis is an infectious disease characterized by excessive inflammation and coagulation that is linked to more severe disease pathology, organ failure, and fatality. The plasma contact system is a protein cascade in the blood that can be activated by bacteria and contributes to both inflammation and coagulation.
OBJECTIVES
To determine if inhibiting the plasma contact system by targeting high-molecular-weight kininogen (HK) can exert a protective effect on bacteria-induced coagulation.
METHODS
Polymicrobial cecal slurry (CS) was prepared from donor mice and used for ex vivo and in vivo experiments. CS was used in vivo to establish a murine model of polymicrobial sepsis. CS was incubated with mouse or human plasma ex vivo. Contact system activation was assessed by Western blot, and clotting was assessed spectroscopically. Our monoclonal antihuman HK antibody, 3E8, was used to determine how contact system inhibition could delay CS-induced coagulation ex vivo.
RESULTS
Polymicrobial CS activated the plasma contact system in vivo in mice and ex vivo in both mouse and human plasma. CS promoted coagulation in mouse and human plasma ex vivo. Treatment with our 3E8 anti-HK antibody protected against CS-induced contact system activation and coagulation.
CONCLUSION
The plasma contact system was activated in the CS model of polymicrobial sepsis. Targeting HK in polymicrobial sepsis may have beneficial effects in limiting excessive coagulation and could represent a novel therapeutic avenue to promote survival in sepsis.
背景
多微生物败血症是一种传染病，其特征为过度炎症反应和凝血，与更严重的疾病病理、器官衰竭及死亡相关。血浆接触系统是血液中的一种蛋白质级联反应，可被细菌激活，在炎症和凝血过程中均发挥作用。
目的
确定通过靶向高分子量激肽原（HK）抑制血浆接触系统是否能对细菌诱导的凝血产生保护作用。
方法
从供体小鼠制备多微生物盲肠灌洗液（CS），用于体外和体内实验。CS用于在体内建立多微生物败血症小鼠模型。CS在体外与小鼠或人血浆孵育。通过蛋白质印迹法评估接触系统激活情况，通过光谱法评估凝血情况。我们的单克隆抗人HK抗体3E8用于确定抑制接触系统如何在体外延迟CS诱导的凝血。
结果
多微生物CS在体内激活小鼠血浆接触系统，在体外激活小鼠和人血浆接触系统。CS在体外促进小鼠和人血浆凝血。用我们的3E8抗HK抗体治疗可防止CS诱导的接触系统激活和凝血。
结论
在多微生物败血症的CS模型中血浆接触系统被激活。在多微生物败血症中靶向HK可能对限制过度凝血具有有益作用，并且可能代表促进败血症患者生存的一种新治疗途径。
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