C4b-binding protein exacerbates the host response to Escherichia coli

Area of Science:

• Coagulation and Thrombosis
• Inflammation and Immunology
• Vascular Biology

Background:

• Activated protein C (APC) is a key anticoagulant, requiring protein S for its function.
• C4b binding protein (C4bBP) neutralizes protein S anticoagulant activity by forming a complex.
• Elevated C4bBP during inflammation can cause acquired functional protein S deficiency, potentially leading to a hypercoagulable state.

Purpose of the Study:

• To investigate the role of C4bBP-mediated inhibition of protein S activity in the host response to Escherichia coli infusion.
• To determine if elevated C4bBP contributes to hypercoagulability and organ damage during inflammation.

Main Methods:

• Experimental model using baboons infused with sublethal or lethal doses of E. coli.
• Groups included E. coli challenge alone, C4bBP infusion alone, E. coli with C4bBP, and E. coli with C4bBP and protein S.
• Physiological parameters monitored included fibrinogen consumption, organ damage, and tumor necrosis factor (TNF) levels.

Main Results:

• Sublethal E. coli infusion alone caused an acute-phase response without significant damage.
• Co-infusion of E. coli and C4bBP led to rapid fibrinogen consumption, systemic organ damage, detectable TNF, and death, mimicking lethal E. coli infusion.
• Supplementation with protein S in the presence of C4bBP and E. coli prevented these adverse effects.

Conclusions:

• Elevated C4bBP during inflammation can induce acquired protein S deficiency, contributing to fibrinogen consumption and vascular damage.
• This vascular damage may be linked to enhanced elaboration of cytokines such as TNF.
• Restoring protein S levels can mitigate the pro-coagulant and damaging effects of C4bBP during inflammatory responses.