title: Effect of supraphysiologic levels of C1-inhibitor on the classical, lectin and alternative pathways of complement.
abstract: C1-inhibitor is increasingly used experimentally and clinically in inflammatory conditions like septicemia and ischemia-reperfusion injury. Several mechanisms may account for the anti-inflammatory effects of C1-inhibitor, including inhibition of complement. The aim of the present study was to investigate and compare the supraphysiologic effect of C1-inhibitor on the three complement pathways. Novel assays for specific evaluation of the classical, lectin and alternative pathways were employed using normal human serum supplemented with increasing concentrations of C1-inhibitor. Solid-phase classical- and lectin pathway activation was dose-dependently and significantly reduced up to 85% in the range of 2-28 times physiologic C1-inhibitor concentration. The lectin pathway was more potently inhibited than the classical at low doses. A functional lectin pathway assay demonstrated a significant reduction of C4 deposition up to 86% even at low concentration of C1-inhibitor and documented the effect to be at the level of MBL/MASPs. In contrast, C1-inhibitor had no effect on solid-phase alternative pathway activation, but significantly reduced cobra venom factor-induced fluid-phase activation up to 88%. The negative controls albumin and IgG had no effect on complement activation. The positive inhibitory controls compstatin (C3 inhibition), EDTA- or MBL-deficient sera reduced complement activation by 82-100%. We conclude that C1-inhibitor in high physiologic doses differentially inhibits all three-complement pathways. The inhibition pattern was strikingly different in the classical and lectin pathway, compared to the alternative. Previous studies interpreting the effects of C1-inhibitor as only due to classical pathway inhibition needs reconsideration. The data has implications for the therapeutic use of C1-inhibitor.
authors.affiliation: Department of Anesthesiology, Nordland Hospital, N-8092 Bodø, Norway; University of Tromsø, Norway. erikwn@fagmed.uit.no
authors.forename: Erik Waage
authors.initials: EW
authors.lastname: Nielsen
authors.forename: Christian
authors.initials: C
authors.lastname: Waage
authors.forename: Hilde
authors.initials: H
authors.lastname: Fure
authors.forename: Ole L
authors.initials: OL
authors.lastname: Brekke
authors.forename: Georgia
authors.initials: G
authors.lastname: Sfyroera
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: Tom E
authors.initials: TE
authors.lastname: Mollnes
mesh_terms: D050718:Complement C1 Inhibitor Protein / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003181:Complement C4 / Q000737:chemistry / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000187:drug effects* / Q000502:physiology; D003171:Complement Pathway, Classical / Q000187:drug effects / Q000502:physiology; D037582:Complement Pathway, Mannose-Binding Lectin / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D037601:Mannose-Binding Lectin / Q000737:chemistry* / Q000378:metabolism; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000737:chemistry* / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism
chemical_list: D050718:Complement C1 Inhibitor Protein; D003181:Complement C4; D037601:Mannose-Binding Lectin; D050606:Mannose-Binding Protein-Associated Serine Proteases