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During sepsis, gram-negative bacteria induce robust inflammation primarily via lipopolysacharride (LPS) signaling through TLR4, a process that involves the glycosylphosphatidylinositol (GPI)-anchored receptor CD14 transferring LPS to the Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD-2) complex. Sepsis also triggers the onset of disseminated intravascular coagulation and consumptive coagulopathy. We investigated the effect of CD14 blockade on sepsis-induced coagulopathy, inflammation, organ dysfunction, and mortality. We used a baboon model of lethal Escherichia (E) coli sepsis to study two experimental groups (n = 5): (a) E coli challenge; (b) E coli challenge plus anti-CD14 (23G4) inhibitory antibody administered as an intravenous bolus 30 minutes before the E coli. Following anti-CD14 treatment, two animals reached the 7-day end-point survivor criteria, while three animals had a significantly prolonged survival as compared to the non-treated animals that developed multiple organ failure and died within 30 hours. Anti-CD14 reduced the activation of coagulation through inhibition of tissue factor-dependent pathway, especially in the survivors, and enhanced the fibrinolysis due to strong inhibition of plasminogen activator inhibitor 1. The treatment prevented the robust complement activation induced by E coli, as shown by significantly decreased C3b, C5a, and sC5b-9. Vital signs, organ function biomarkers, bacteria clearance, and leukocyte and fibrinogen consumption were all improved at varying levels. Anti-CD14 reduced neutrophil activation, cell death, LPS levels, and pro-inflammatory cytokines (tumor necrosis factor, interleukin (IL)-6, IL-1β, IL-8, interferon gamma, monocyte chemoattractant protein-1), more significantly in the survivors than non-surviving animals. Our results highlight the crosstalk between coagulation/fibrinolysis, inflammation, and complement systems and suggest a protective role of anti-CD14 treatment in E coli sepsis. © 2020 International Society on Thrombosis and Haemostasis.

Citation

Ravi S Keshari, Robert Silasi, Narcis I Popescu, Girija Regmi, Hala Chaaban, John D Lambris, Cristina Lupu, Tom E Mollnes, Florea Lupu. CD14 inhibition improves survival and attenuates thrombo-inflammation and cardiopulmonary dysfunction in a baboon model of Escherichia coli sepsis. Journal of thrombosis and haemostasis : JTH. 2021 Feb;19(2):429-443

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PMID: 33174372

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