Complement and the TLR family constitute two important branches of innate immunity. We previously showed attenuating effects on
inflammation and thromogenicity by inhibiting the TLR coreceptor CD14 in porcine
sepsis. In the present study, we explored the effect of the C5 and
leukotriene B4 inhibitor Ornithodoros moubata
complement inhibitor (OmCI; also known as coversin) alone and combined with anti-CD14 on the early inflammatory,
hemostatic, and hemodynamic responses in porcine Escherichia coli-induced
sepsis. Pigs were randomly allocated to negative controls (n = 6), positive controls (n = 8), intervention with OmCI (n = 8), or with OmCI and anti-CD14 (n = 8). OmCI ablated C5 activation and formation of the
terminal complement complex and significantly decreased
leukotriene B4 levels in septic pigs. Granulocyte
tissue factor expression, formation of
thrombin-
antithrombin complexes (p < 0.001), and formation of TNF-α and
IL-6 (p < 0.05) were efficiently inhibited by OmCI alone and abolished or strongly attenuated by the combination of OmCI and anti-CD14 (p < 0.001 for all). Additionally, the combined
therapy attenuated the formation of
plasminogen activator inhibitor-1 (p < 0.05), IL-1β, and
IL-8, increased the formation of
IL-10, and abolished the expression of wCD11R3 (CD11b) and the fall in neutrophil cell count (p < 0.001 for all). Finally, OmCI combined with anti-CD14 delayed increases in heart rate by 60 min (p < 0.05) and mean pulmonary artery pressure by 30 min (p < 0.01). Ex vivo studies confirmed the additional effect of combining anti-CD14 with OmCI. In conclusion, upstream inhibition of the key innate immunity molecules, C5 and CD14, is a potential broad-acting treatment regimen in
sepsis as it efficiently attenuated
inflammation and thrombogenicity and delayed hemodynamic changes.