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Abstract
IntroductionSepsis 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.MethodsNorwegian 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.ResultsCombined 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.ConclusionsCombined inhibition of C5 and CD14 significantly improved survival, hemodynamic parameters and inflammation in a blinded, randomized trial of porcine polymicrobial sepsis.
Highlights
Sepsis is an exaggerated and dysfunctional immune response to infection
Effect of complement activation on treatment and survival Seven of the eight animals in the untreated group that died before scheduled euthanasia had exponentially increased Soluble terminal C5b-9 complement complex (TCC) (sC5b-9) levels (range 444–3713 complement arbitrary units (CAU)/L). (Fig. 3a). sC5b-9 levels were significantly higher in the untreated group compared to treated animals (p < 0.001, Fig. 3b)
All but one animal had a net decrease in sC5b-9 levels to below baseline values throughout the experiment, consistent with a complete blockade of component 5 (C5) and no substrate for sC5b-9 generation
Summary
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. Treated too late, sepsis will progress to a systemically uncontrolled, dysregulated immune response leading to vascular instability, capillary leakage, septic cardiomyopathy, shock, disseminated intravascular coagulation, and acute kidney and respiratory failure. This multiple organ failure (MOF) is associated with high costs. There is a need for adequate experimental models of sepsis as the most commonly used animal models have failed to mimic human sepsis [6, 7].
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