Combined inhibition of complement and CD14 improved outcome in porcine polymicrobial sepsis.

Abstract

INTRODUCTION:

Sepsis is an exaggerated and dysfunctional immune response to infection. Activation of innate immunity recognition systems including complement and the Toll-like receptor family initiate this disproportionate inflammatory response. The aim of this study was to explore the effect of combined inhibition of the complement component C5 and the Toll-like receptor co-factor CD14 on survival, hemodynamic parameters and systemic inflammation including complement activation in a clinically relevant porcine model of polymicrobial sepsis.

METHODS:

Norwegian landrace piglets (4 ± 0.5 kg) were blindly randomized to a treatment group (n = 12) receiving the C5 inhibitor coversin (OmCI) and anti-CD14 or to a positive control group (n = 12) receiving saline. Under anesthesia, sepsis was induced by a 2 cm cecal incision and the piglets were monitored in standard intensive care for 8 hours. Three sham piglets had a laparotomy without cecal incision or treatment. Complement activation was measured as sC5b-9 using enzyme immunoassay. Cytokines were measured with multiplex technology.

RESULTS:

Combined C5 and CD14 inhibition significantly improved survival (p = 0.03). Nine piglets survived in the treatment group and four in the control group. The treatment group had significantly lower pulmonary artery pressure (p = 0.04) and ratio of pulmonary artery pressure to systemic artery pressure (p < 0.001). Plasma sC5b-9 levels were significantly lower in the treatment group (p < 0.001) and correlated significantly with mortality (p = 0.006). IL-8 and IL-10 were significantly (p < 0.05) lower in the treatment group.

CONCLUSIONS:

Combined inhibition of C5 and CD14 significantly improved survival, hemodynamic parameters and inflammation in a blinded, randomized trial of porcine polymicrobial sepsis.

• Authors: Espen W Skjeflo, Caroline Sagatun, Knut Dybwik, Sturla Aam, Sven H Urving, Miles A Nunn, Hilde Fure, Corinna Lau, Ole-Lars Brekke, Markus Huber-Lang, Terje Espevik, Andreas Barratt-Due, Erik W Nielsen, Tom E Mollnes
• Journal: Critical care (London, England) (Crit Care) Vol. 19 Pg. 415 (Nov 27 2015) ISSN: 1466-609X [Electronic] England
• PMID: 26612199 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Complement C5
• Lipopolysaccharide Receptors
• Toll-Like Receptors

Topics

• Animals
• Complement C5 (antagonists & inhibitors)
• Inflammation (blood, mortality)
• Lipopolysaccharide Receptors (metabolism)
• Sepsis (drug therapy, metabolism, microbiology, mortality)
• Swine
• Toll-Like Receptors (immunology, metabolism)