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.

SUBMITTER: Badimon A 

PROVIDER: S-EPMC12422282 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature