title: Combined inhibition of complement and CD14 improved outcome in porcine polymicrobial sepsis.
abstract: BACKGROUND
  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.affiliation: Research Laboratory, Nordland Hospital, Prinsens Gate 164, 8092, Bodø, Norway. espenwskjeflo@gmail.com.|Faculty of Health Sciences, K. G. Jebsen TREC, University of Tromsø, 9037, Tromsø, Norway. espenwskjeflo@gmail.com.
authors.forename: Espen W
authors.initials: EW
authors.lastname: Skjeflo
authors.affiliation: Department of Surgery, Nordland Hospital, Prinsens Gate 164, 8092, Bodø, Norway. c.sagatun@gmail.com.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sagatun
authors.affiliation: Department of Anestesiology, Nordland Hospital, Prinsens Gate 164, 8092, Bodø, Norway. kdybwik@gmail.com.|Faculty of Professional Studies, University of Nordland, Universitetsaleen 11, 8049, Bodø, Norway. kdybwik@gmail.com.
authors.forename: Knut
authors.initials: K
authors.lastname: Dybwik
authors.affiliation: Faculty of Medicine, Ludwig Maximillian University, Professor Huber Platz 2, 80539, Munich, Germany. sturla.aam@gmail.com.
authors.forename: Sturla
authors.initials: S
authors.lastname: Aam
authors.affiliation: Department of Anestesiology, Nordland Hospital, Prinsens Gate 164, 8092, Bodø, Norway. shurving@gmail.com.
authors.forename: Sven H
authors.initials: SH
authors.lastname: Urving
authors.affiliation: Volution Immuno Pharmaceuticals Limited, 5 Argosy Court, Whitley Business Park, Coventry, CV3 4GA, UK. miles.nunn@gmail.com.
authors.forename: Miles A
authors.initials: MA
authors.lastname: Nunn
authors.affiliation: Research Laboratory, Nordland Hospital, Prinsens Gate 164, 8092, Bodø, Norway. Hilde.Fure@nlsh.no.
authors.forename: Hilde
authors.initials: H
authors.lastname: Fure
authors.affiliation: Research Laboratory, Nordland Hospital, Prinsens Gate 164, 8092, Bodø, Norway. Corinna.Lau@nlsh.no.
authors.forename: Corinna
authors.initials: C
authors.lastname: Lau
authors.affiliation: Research Laboratory, Nordland Hospital, Prinsens Gate 164, 8092, Bodø, Norway. Ole.Lars.Brekke@nlsh.no.|Faculty of Health Sciences, K. G. Jebsen TREC, University of Tromsø, 9037, Tromsø, Norway. Ole.Lars.Brekke@nlsh.no.
authors.forename: Ole-Lars
authors.initials: OL
authors.lastname: Brekke
authors.affiliation: Department of Traumatology, Center of Surgery, University of Ulm, Albert Einstein Allee 23, 89081, Ulm, Germany. Markus.Huber-Lang@uniklinik-ulm.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Huber-Lang
authors.affiliation: Centre of Molecular Inflammation Research, and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Høgskoleringen 1, 7491, Trondheim, Norway. terje.espevik@ntnu.no.
authors.forename: Terje
authors.initials: T
authors.lastname: Espevik
authors.affiliation: Department of Immunology, Oslo University Hospital and K.G. Jebsen IRC, University of Oslo, PB 4960 Nydalen, 0424, Oslo, Norway. andreas.barrattdue@gmail.com.|Division of Emergencies and Critical Care, Rikshospitalet, Oslo University Hospital Oslo, Sognsvannsveien 20, 0372, Oslo, Norway. andreas.barrattdue@gmail.com.
authors.forename: Andreas
authors.initials: A
authors.lastname: Barratt-Due
authors.affiliation: Faculty of Health Sciences, K. G. Jebsen TREC, University of Tromsø, 9037, Tromsø, Norway. erik.waage.nielsen@gmail.com.|Department of Anestesiology, Nordland Hospital, Prinsens Gate 164, 8092, Bodø, Norway. erik.waage.nielsen@gmail.com.|Faculty of Professional Studies, University of Nordland, Universitetsaleen 11, 8049, Bodø, Norway. erik.waage.nielsen@gmail.com.|Department of Immunology, Oslo University Hospital and K.G. Jebsen IRC, University of Oslo, PB 4960 Nydalen, 0424, Oslo, Norway. erik.waage.nielsen@gmail.com.
authors.forename: Erik W
authors.initials: EW
authors.lastname: Nielsen
authors.affiliation: Research Laboratory, Nordland Hospital, Prinsens Gate 164, 8092, Bodø, Norway. t.e.mollnes@medisin.uio.no.|Faculty of Health Sciences, K. G. Jebsen TREC, University of Tromsø, 9037, Tromsø, Norway. t.e.mollnes@medisin.uio.no.|Centre of Molecular Inflammation Research, and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Høgskoleringen 1, 7491, Trondheim, Norway. t.e.mollnes@medisin.uio.no.|Department of Immunology, Oslo University Hospital and K.G. Jebsen IRC, University of Oslo, PB 4960 Nydalen, 0424, Oslo, Norway. t.e.mollnes@medisin.uio.no.
authors.forename: Tom E
authors.initials: TE
authors.lastname: Mollnes
mesh_terms: D000818:Animals; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000097:blood / Q000401:mortality; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000401:mortality; D013552:Swine; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism
chemical_list: D003182:Complement C5; D018950:Lipopolysaccharide Receptors; D051193:Toll-Like Receptors