• Air Bubbles Activate Complement and Trigger Hemostasis and C3-Dependent Cytokine Release Ex Vivo in Human Whole Blood 

      Storm, Benjamin; Christiansen, Dorte; Fure, Hilde; Ludviksen, Judith K; Lau, Corinna; Lambris, John D.; Woodruff, Trent M.; Brekke, Ole-Lars; Braaten, Tonje Bjørndal; Nielsen, Erik Waage; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2021-11-03)
      Venous air embolism, which may complicate medical and surgical procedures, activates complement and triggers thromboinflammation. In lepirudin-anticoagulated human whole blood, we examined the effect of air bubbles on complement and its role in thromboinflammation. Whole blood from 16 donors was incubated with air bubbles without or with inhibitors of C3, C5, C5aR1, or CD14. Complement activation, ...
    • Avoiding ambient air in test tubes during incubations of human whole-blood minimizes complement background activation 

      Storm, Benjamin; Christiansen, Dorte; Mollnes, Tom Eirik; Nielsen, Erik Waage (Journal article; Tidsskriftartikkel; Peer reviewed, 2020-10-06)
      <p><i>Background - </i>In vitro, the complement system can be studied in test tubes incubated with anticoagulated human whole-blood. Background activation of complement may mask inflammatory signals. Air bubbles are known to activate complement. We examined if removing ambient air from test tubes before incubation reduced background complement activation. <p><i>Methods - </i>Blood from twelve donors ...
    • Combined inhibition of C5 and CD14 efficiently attenuated the inflammatory response in a porcine model of meningococcal sepsis 

      Hellerud, Bernt C; Orrem, Hilde L.; Dybwik, Knut Gustav; Pischke, Søren Erik; Barratt-Due, Andreas; Castellheim, Albert; Fure, Hilde; Bergseth, Grete; Christiansen, Dorte; Nunn, Miles A.; Espevik, Terje; Lau, Corinna; Brandtzæg, Petter; Nielsen, Erik Waage; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2017-02-27)
      Background<br> Fulminant meningococcal sepsis, characterized by overwhelming innate immune activation, mostly affects young people and causes high mortality. This study aimed to investigate the effect of targeting two key molecules of innate immunity, complement component C5, and co-receptor CD14 in the Toll-like receptor system, on the inflammatory response in meningococcal sepsis.<p> Methods ...
    • Combined inhibition of complement and CD14 attenuates bacteria-induced inflammation in human whole blood more efficiently than antagonizing the toll-like receptor 4-MD2 complex 

      Gustavsen, Alice; Nymo, Stig Haugset; Landsem, Anne; Christiansen, Dorte; Ryan, Liv; Husebye, Harald; Lau, Corinna; Pischke, Søren Erik; Lambris, John D.; Espevik, Terje; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2016-03-14)
      <i>Background</i>: Single inhibition of the Toll-like receptor 4 (TLR4)–MD2 complex failed in treatment of sepsis. CD14 is a coreceptor for several TLRs, including TLR4 and TLR2. The aim of this study was to investigate the effect of single TLR4-MD2 inhibition by using eritoran, compared with the effect of CD14 inhibition alone and combined with the C3 complement inhibitor compstatin (Cp40), on the ...
    • Comparison of cytokine changes in three different lipoprotein apheresis systems in an ex vivo whole blood model 

      Hardersen, Randolf Inge; Enebakk, Terje; Christiansen, Dorte; Ludviksen, Judith K; Mollnes, Tom Eirik; Lappegård, Knut Tore; Hovland, Anders (Journal article; Tidsskriftartikkel; Peer reviewed, 2019-11-29)
      <i>Introduction</i> - Even if proprotein convertase subtilisin/kexin type 9 inhibitors have replaced lipoprotein apheresis in many patients, lipoprotein apheresis still is an important option in homozygous familial hypercholesterolemia, progressive atherosclerosis or when removal of lipoprotein(a) is indicated. Additional possible favorable effects beyond lipid lowering could include changes in ...
    • Complement C3b contributes to Escherichia coli-induced platelet aggregation in human whole blood 

      Landsem, Anne; Emblem, Åse; Lau, Corinna; Christiansen, Dorte; Gerogianni, Alexandra; Karlsen, Bård Ove; Mollnes, Tom Eirik; Nilsson, Per; Brekke, Ole Lars (Journal article; Tidsskriftartikkel; Peer reviewed, 2022-12-14)
      We found that compstatin, which inhibits the cleavage of complement component C3 to its components C3a and C3b, reduced the E. coli-induced platelet aggregation by 42%-76% (p = 0.0417). This C3-dependent aggregation was not C3a-mediated as neither inhibition of C3a using a blocking antibody or a C3a receptor antagonist, nor the addition of purified C3a had any effects. In contrast, a C3b-blocking ...
    • Complement component 5 does not interfere with physiological hemostasis but is essential for Escherichia coli-induced coagulation accompanied by Toll-like receptor 4 

      Landsem, Anne; Fure, Hilde; Ludviksen, Judith K; Christiansen, Dorte; Lau, Corinna; Mathisen, Monica Dammen; Bergseth, Grete; Nymo, Stig Haugset; Lappegård, Knut Tore; Woodruff, T. M.; Espevik, Terje; Mollnes, Tom Eirik; Brekke, Ole-Lars (Journal article; Tidsskriftartikkel; Peer reviewed, 2018-12-19)
      There is a close cross‐talk between complement, Toll‐like receptors (TLRs) and coagulation. The role of the central complement component 5 (C5) in physiological and pathophysiological hemostasis has not, however, been fully elucidated. This study examined the effects of C5 in normal hemostasis and in <i>Escherichia coli</i>‐induced coagulation and tissue factor (TF) up‐regulation. Fresh whole blood ...
    • Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn 

      Hallstensen, Randi; Bergseth, Grete; Foss, Stian; Jæger, Steinar; Gedde-Dahl, Thobias; Holt, jan; Christiansen, Dorte; Lau, Corinna; Brekke, Ole Lars; Armstrong, Elina; Stefanovic, Vedran; Andersen, Jan Terje; Sandlie, Inger; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2015-11-13)
      Eculizumab is a humanized IgG2/4 chimeric anti-complement C5 antibody used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome. The aim of this study was to evaluate whether or not the complement activity in newborns from pregnant women who receive eculizumab is impaired. A novel eculizumab-C5 complex (E-C5) specific assay was developed and ...
    • Effect of the anticoagulant, storage time and temperature of blood samples on the concentrations of 27 multiplex assayed cytokines – Consequences for defining reference values in healthy humans 

      Hennø, Linda Torrissen; Storjord, Elin; Christiansen, Dorte; Bergseth, Grete; Ludviksen, Judith K; Fure, Hilde; Barene, Svein; Nielsen, Erik Waage; Mollnes, Tom Eirik; Brekke, Ole Lars (Journal article; Tidsskriftartikkel; Peer reviewed, 2017-06-06)
      Cytokines are potentially useful biomarkers of sepsis and other inflammatory conditions. Many cytokines can be released by leukocytes and platelets after sampling. The sampling and processing techniques are consequently critically important to measure the <i>in vivo</i> levels. We therefore examined the effects of four different anticoagulants, EDTA, citrate, lepirudin, heparin compared to serum, ...
    • Gas embolism during surgery. A complement mediated condition? 

      Storm, Benjamin Stage; Christiansen, Dorte; Dybwik, Knut; Mollnes, Tom Eirik; Nielsen, Erik Waage (Journal article; Tidsskriftartikkel; Peer reviewed, 2017-10-01)
      <p><i>Introduction</i>: Venous air embolism (VAE) may arise during surgical procedures. VAE might be complicated with a systemic inflammatory response, disseminated intervascular coagulation, multi-organ failure and cardiovascular collapse. During a short time-span, three patients at our institution developed signs of VAE in conjunction with gynecological surgery. One died, one developed severe ...
    • Granulocyte and monocyte CD11b expression during plasma separation is dependent on complement factor 5 (C5) – an ex vivo study with blood from a C5-deficient individual 

      Hardersen, Randolf Inge; Enebakk, Terje; Christiansen, Dorte; Bergseth, Grete; Brekke, Ole-Lars; Mollnes, Tom Eirik; Lappegård, Knut Tore; Hovland, Anders (Journal article; Tidsskriftartikkel, 2018)
      The aim of the study was to investigate the role of complement factor 5 (C5) in reactions elicited by plasma separation using blood from a C5‐deficient (C5D) individual, comparing it to C5‐deficient blood reconstituted with C5 (C5DR) and blood from healthy donors. Blood was circulated through an <i>ex vivo</i> plasma separation model. Leukocyte CD11b expression and leukocyte–platelet conjugates were ...
    • Key role of the number of complement receptor 1 on erythrocytes for binding of Escherichia coli to erythrocytes and for leukocyte phagocytosis and oxidative burst in human whole blood 

      Brekke, Ole-Lars; Christiansen, Dorte; Kisserli, Aymric; Fure, Hilde; Dahl, Jim André; Donvito, Béatrice; Reveil, Brigitte; Ludviksen, Judith K; Tabary, Thierry; Mollnes, Tom Eirik; Cohen, Jacques H.M. (Journal article; Tidsskriftartikkel, 2019-07-25)
      <i>Aim</i> - To study the role of complement receptor 1 (CR1) for binding of <i>Escherichia coli (E. coli)</i> to erythrocytes, for leukocyte phagocytosis, oxidative burst and complement activation in human whole blood from a CR1 deficient (CR1D) patient and healthy controls with low, medium and high CR1 numbers.<p> <p><i>Methods</i> - Alexa-labelled bacteria were used to quantify ...
    • Open chest and pericardium facilitate transpulmonary passage of venous air emboli 

      Storm, Benjamin; Halvorsen, Per Steinar; Skulstad, Helge; Dybwik, Knut Gustav; Schjalm, Camilla; Christiansen, Dorte; Wisløff-Aase, Kristin; Fosse, Erik; Braaten, Tonje Bjørndal; Nielsen, Erik Waage; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2021-02-17)
      <p><i>Background:</i> Transpulmonary passage of air emboli can lead to fatal brain- and myocardial infarctions. We studied whether pigs with open chest and pericardium had a greater transpulmonary passage of venous air emboli than pigs with closed thorax. <p><i>Methods:</i> We allocated pigs with verified closed foramen ovale to venous air infusion with either open chest with sternotomy and opening ...
    • Phagocytosis of live and dead Escherichia coli and Staphylococcus aureus in human whole blood is markedly reduced by combined inhibition of C5aR1 and CD14 

      Skjeflo, Espen Waage; Christiansen, Dorte; Landsem, Anne; Stenvik, Jørgen; Woodruff, T. M.; Espevik, Terje; Nielsen, Erik Waage; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2019-05-15)
      <i>Background</i> - Sepsis is a dysregulated host response to infection. The aim of this study was to investigate the effects of complement- and CD14 inhibition on phagocytosis of live and dead Gram-negative and Gram-positive bacteria in human whole blood.<p> <p><i>Methods</i> - Lepirudin-anticoagulated blood was incubated with live or dead <i>E. coli</i> or <i>S. aureus</i> at 37 °C for 120 min ...
    • Quantification of Porcine Complement Activation Fragment C3a by a Neoepitope-Based Enzyme-Linked Immunosorbent Assay 

      Nilsson, Per; Pettersen, Kristin; Oppermann, Martin; Skjeflo, Espen Waage; Fure, Hilde; Christiansen, Dorte; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2021-04-14)
      Enzyme-linked immunosorbent assay (ELISA) enables fast and simple quantification of analytes in the pico- to nanogram range in complex samples. Here, we describe an ELISA for the detection of porcine C3a as a marker for complement activation. Antibody specificity is critical for a robust assay. This assay is based on a pair of antibodies specific for the porcine C3a molecule and thus does not react ...
    • Staphylococcus aureus-induced complement activation promotes tissue factor-mediated coagulation 

      Skjeflo, Espen Waage; Christiansen, Dorte; Fure, Hilde; Ludviksen, Judith K; Woodruff, Trent M.; Espevik, Terje; Nielsen, Erik Waage; Brekke, Ole-Lars; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2018-02-13)
      <p><i>Background - </i>There is extensive cross‐talk between the complement system, the Toll‐like receptors (TLRs), and hemostasis. Consumptive coagulopathy is a hallmark of sepsis, and is often mediated through increased tissue factor (TF) expression. <p><i>Objectives - </i>To study the relative roles of complement, TLRs and TF in <i>Staphylococcus aureus</i>‐induced coagulation. <p><i>Methods - ...
    • Venous Air Embolism Activates Complement C3 Without Corresponding C5 Activation and Trigger Thromboinflammation in Pigs 

      Storm, Benjamin; Ludviksen, Judith K; Christiansen, Dorte; Fure, Hilde; Pettersen, Kristin; Landsem, Anne; Nilsen, Bent Aksel; Dybwik, Knut Gustav; Braaten, Tonje; Nielsen, Erik Waage; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2022-03-15)
      Introduction: Air embolism may complicate invasive medical procedures. Bubbles trigger complement C3-mediated cytokine release, coagulation, and platelet activation in vitro in human whole blood. Since these findings have not been verified in vivo, we aimed to examine the effects of air embolism in pigs on thromboinflammation.<p> <p>Methods: Forty-five landrace pigs, average 17 kg (range 8.5-30), ...