title: Organ inflammation in porcine Escherichia coli sepsis is markedly attenuated by combined inhibition of C5 and CD14.
abstract: Sepsis is an infection-induced systemic inflammatory syndrome, potentially causing organ failure. We previously showed attenuating effects on inflammation, thrombogenicity and haemodynamics by inhibiting the Toll-like receptor co-factor CD14 and complement factor C5 in a porcine Escherichia coli-induced sepsis model. The present study explored the effect on organ inflammation in these pigs. Tissue samples were examined from the combined treatment group (n = 8), the positive (n = 8) and negative (n = 6) control groups after 4h of sepsis. Inflammatory biomarkers were measured using ELISA, multiplex and qPCR analysis. Combined inhibition of C5 and CD14 markedly attenuated IL-1β by 31-66% (P < 0.05) and IL-6 by 54-96% (P < 0.01) in liver, kidney, lung and spleen; IL-8 by 65-100% in kidney, lung, spleen, and heart (P < 0.05) and MCP-1 by 46-69% in liver, kidney, spleen and heart (P < 0.05). Combined inhibition significantly attenuated tissue factor mRNA upregulation in spleen (P < 0.05) and IP-10 mRNA upregulation in four out of five organs. Finally, C5aR mRNA downregulation was prevented in heart and kidney (P < 0.05). Combined inhibition of C5 and CD14 thus markedly attenuated inflammatory responses in all organs examined. The anti-inflammatory effects observed in lung and heart may explain the delayed haemodynamic disturbances observed in septic pigs receiving combined inhibition of C5 and CD14.
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen IRC, University of Oslo, Oslo, Norway.
authors.forename: Kjetil H
authors.initials: KH
authors.lastname: Egge
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen IRC, University of Oslo, Oslo, Norway; Department of Transplantation Medicine, Section for Transplant Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Ebbe B
authors.initials: EB
authors.lastname: Thorgersen
authors.affiliation: Interventional Center, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway.
authors.forename: Søren E
authors.initials: SE
authors.lastname: Pischke
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen IRC, University of Oslo, Oslo, Norway.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Lindstad
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen IRC, University of Oslo, Oslo, Norway.
authors.forename: Anne
authors.initials: A
authors.lastname: Pharo
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Anjan K
authors.initials: AK
authors.lastname: Bongoni
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Rieben
authors.affiliation: Volution Immuno Pharmaceuticals Limited SA, London, United Kingdom.
authors.forename: Miles A
authors.initials: MA
authors.lastname: Nunn
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen IRC, University of Oslo, Oslo, Norway.
authors.forename: Andreas
authors.initials: A
authors.lastname: Barratt-Due
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen IRC, University of Oslo, Oslo, Norway; Research Laboratory, Nordland Hospital and Faculty of Health Sciences, K. G. Jebsen TREC, University of Tromsø, Tromsø, Norway; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: t.e.mollnes@medisin.uio.no.
authors.forename: Tom E
authors.initials: TE
authors.lastname: Mollnes
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000276:immunology*; D004927:Escherichia coli Infections / Q000276:immunology / Q000628:therapy*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000628:therapy; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D009102:Multiple Organ Failure / Q000382:microbiology / Q000628:therapy*; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000628:therapy*; D013552:Swine
chemical_list: D018932:Chemokine CCL2; D003182:Complement C5; D053583:Interleukin-1beta; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D044087:Receptor, Anaphylatoxin C5a
keywords: CD14; Complement; Inflammation; Porcine; Sepsis; Tissue