An antibody targeting high-molecular-weight kininogen blocks contact system activation in a model of polymicrobial sepsis.

Abstract

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.