• 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, ...
    • Blood Transcriptome Analysis of Septic Patients Reveals a Long Non-Coding Alu-RNA in the Complement C5a Receptor 1 Gene 

      Emblem, Åse; Knutsen, Erik; Jørgensen, Tor Erik; Fure, Hilde; Johansen, Steinar Daae; Brekke, Ole Lars; Mollnes, Tom Eirik; Karlsen, Bård Ove (Journal article; Tidsskriftartikkel; Peer reviewed, 2022-03-29)
      Many severe inflammation conditions are complement-dependent with the complement component C5a-C5aR1 axis as an important driver. At the RNA level, the blood transcriptome undergoes programmed expression of coding and long non-coding RNAs to combat invading microorganisms. Understanding the expression of long non-coding RNAs containing Alu elements in inflammation is important for reconstructing ...
    • Blood Transcriptome Analysis of Septic Patients Reveals a Long Non-Coding Alu-RNA in the Complement C5a Receptor 1 Gene 

      Emblem, Åse; Knutsen, Erik; Jørgensen, Tor Erik; Fure, Hilde; Johansen, Steinar Daae; Brekke, Ole Lars; Mollnes, Tom Eirik; Karlsen, Bård Ove (Journal article; Tidsskriftartikkel; Peer reviewed, 2022-03-29)
      Many severe inflammation conditions are complement-dependent with the complement component C5a-C5aR1 axis as an important driver. At the RNA level, the blood transcriptome undergoes programmed expression of coding and long non-coding RNAs to combat invading microorganisms. Understanding the expression of long non-coding RNAs containing Alu elements in inflammation is important for reconstructing ...
    • Bradykinin-Induced Shock Increase Exhaled Nitric Oxide, Complement Activation and Cytokine Production in Pigs 

      Seip, Knut Fredrik; Evjenth, Bjørg; Hovland, Anders; Dybwik, Knut Gustav; Johansen, Harald Thidemann; Fure, Hilde; Mollnes, Tom Eirik; Nielsen, Erik Waage (Journal article; Tidsskriftartikkel; Peer reviewed, 2016-03-04)
      Bradykinin is an important mediator in blood pressure regulation, ischemic precondition and capillary leakage, allergy, anaphylaxis, inflammation, and nociception, at least partly via the generation of nitric oxide (NO). Macrophages are particularly abundant in the porcine lung circulation. Upon bradykinin binding macrophages release cytokines and endothelial ...
    • CD14 and complement crosstalk and largely mediate the transcriptional response to Escherichia coli in human whole blood as revealed by DNA microarray 

      Lau, Corinna; Nygård, Ståle; Fure, Hilde; Olstad, Ole Kristoffer; Holden, Marit; Lappegård, Knut Tore; Brekke, Ole Lars; Espevik, Terje; Hovig, Johannes Eivind; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2015-02-23)
      Systemic inflammation like in sepsis is still lacking specific diagnostic markers and effective therapeutics. The first line of defense against intruding pathogens and endogenous damage signals is pattern recognition by e.g., complement and Toll-like receptors (TLR). Combined inhibition of a key complement component (C3 and C5) and TLR-co-receptor CD14 has been shown to attenuate certain systemic ...
    • 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 improved outcome in porcine polymicrobial sepsis 

      Skjeflo, Espen Waage; Sagatun, Caroline; Dybwik, Knut; Aam, Sturla; Urving, Sven Haakon; Nunn, Miles A.; Fure, Hilde; Lau, Corinna; Brekke, Ole Lars; Huber-Lang, Markus; Barratt-Due, Andreas; Nielsen, Erik Waage; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2015-11-27)
      Introduction: 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, ...
    • 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 ...
    • A conformational change of complement C5 is required for thrombin-mediated cleavage, revealed by a novel ex vivo human whole blood model preserving full thrombin activity 

      Nilsson, Per; Johnson, Christina; Quach, Huy Quang; Macpherson, Alex; Durrant, Oliver; Pischke, Soeren; Fure, Hilde; Landsem, Anne; Bergseth, Grete; Schjalm, Camilla; Haugaard-Kedström, Linda M.; Huber-Lang, Markus; van den Elsen, Jean; Brekke, Ole-Lars; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2021-09-15)
      Thrombin activation of C5 connects thrombosis to inflammation. Complement research in whole blood ex vivo necessitates anticoagulation, which potentially interferes with the inflammatory modulation by thrombin. We challenged the concept of thrombin as an activator of native C5 by analyzing complement activation and C5 cleavage in human whole blood anticoagulated with Gly-Pro-Arg-Pro (GPRP), a peptide ...
    • Dental and Periodontal Health in Acute Intermittent Porphyria 

      Storjord, Elin; Airila-Månsson, Stella; Karlsen, Katarzyna; Madsen, Martin Ragnar Skjerve; Dahl, Jim André; Landsem, Anne; Fure, Hilde; Ludviksen, Judith K; Fjøse, Johannes Østrem; Dickey, Amy K.; Karlsen, Bård Ove; Nielsen, Erik Waage; Mollnes, Tom Eirik; Brekke, Ole Lars (Journal article; Tidsskriftartikkel; Peer reviewed, 2022-08-19)
      In the inherited metabolic disorder acute intermittent porphyria (AIP), high sugar intake prevents porphyric attacks due to the glucose effect and the following high insulin levels that may lower AIP disease activity. Insulin resistance is a known risk factor for periodontitis and sugar changes diabetogenic hormones and affects dental health. We hypothesized differences in homeostasis model ...
    • 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, ...
    • Gene expression profiling of Gram-negative bacteria-induced inflammation in human whole blood: The role of complement and CD14-mediated innate immune response 

      Lau, Corinna; Olstad, Ole Kristoffer; Holden, Marit; Nygård, Ståle; Fure, Hilde; Lappegård, Knut Tore; Brekke, Ole Lars; Espevik, Terje; Hovig, Johannes Eivind; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2015-05-30)
      Non-sterile pathogen-induced sepsis and sterile inflammation like in trauma or ischemia–reperfusion injury may both coincide with the life threatening systemic inflammatory response syndrome and multi-organ failure. Consequently, there is an urgent need for specific biomarkers in order to distinguish sepsis from sterile conditions. The overall aim of this study was to uncover putative sepsis ...
    • Intestinal inflammatory profile shows increase in a diversity of biomarkers in irritable bowel syndrome 

      Berg, Leif Kyrre; Goll, Rasmus; Fagerli, Erik; Ludviksen, Judith K; Fure, Hilde; Odd Sverre, Moen; Sørbye, Sveinung; Mollnes, Tom Eirik; Florholmen, Jon (Journal article; Tidsskriftartikkel; Peer reviewed, 2020-04-24)
      Background: It has been proposed that irritable bowel syndrome (IBS) is a low-grade mucosal inflammatory disease. <p> <p>Objective: To characterize the intestinal inflammatory profile in IBS patients with or without fructose intolerance.<p> <p>Design: Patients referred to colonoscopy with IBS complaints were screened for participation. IBS patients diagnosed according to the Rome II criteria ...
    • 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 ...
    • NHDL, a recombinant VL/VH hybrid antibody control for IgG2/4 antibodies. 

      Lau, Corinna; McAdam, MB; Bergseth, G; Grevys, Algirdas; Bruun, JA; Ludviksen, Judith K; Fure, Hilde; Espevik, Terje; Moen, A; Andersen, Jan Terje; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2019-11-27)
      The mechanism of action of recombinant IgG2/4 antibodies involves blocking of their target without the induction of effector functions. Examples are eculizumab (Soliris®), which is used clinically to block complement factor C5, as well as anti-human CD14 (r18D11) and anti-porcine CD14 (rMIL2) produced in our laboratory. So far, no proper IgG2/4 control antibody has been available for controlled ...
    • A Novel Porcine Model of Ischemia-Reperfusion Injury After Cross-Clamping the Thoracic Aorta Revealed Substantial Cardiopulmonary, Thromboinflammatory and Biochemical Changes Without Effect of C1-Inhibitor Treatment 

      Nielsen, Erik Waage; Miller, Yoav; Brekke, Ole Lars; Grond, Joost; Duong, Anh Hoang; Fure, Hilde; Ludviksen, Judith K; Pettersen, Kristin; Reubsaet, Leon; Solberg, Rigmor; Johansen, Harald Thidemann; Mollnes, Tom Eirik (Journal article; Tidsskriftartikkel; Peer reviewed, 2022-04-01)
      Ischemic injury worsens upon return of blood and innate immunity including the complement system play a central role in ischemia-reperfusion injury (IRI) as in thoracic aortic surgery. Complement component1 inhibitor (C1-INH) has been shown to reduce IRI and is a broad-acting plasma cascade inhibitor. We established a new porcine model of IRI by cross-clamping the thoracic aorta and evaluated the ...
    • 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 ...
    • Sepsis causes right ventricular myocardial inflammation independent of pulmonary hypertension in a porcine sepsis model 

      Pischke, Søren; Hestenes, Siv Merete; Johansen, Harald Thidemann; Fure, Hilde; Bugge, Jan F; Espinoza, Andreas Westenvik; Skulstad, Helge; Edvardsen, Thor; Fosse, Erik; Mollnes, Tom Eirik; Halvorsen, Per Steinar; Nielsen, Erik Waage (Journal article; Tidsskriftartikkel; Peer reviewed, 2019-06-27)
      <i>Introduction</i> - Right ventricular (RV) myocardial dysfunction is a common feature in septic shock. It can worsen outcome, but the etiology is poorly understood. Pulmonary artery hypertension (PAH) plays a part in the pathogenesis of the right heart dysfunction in sepsis but its importance is unknown. In pigs, PAH in sepsis is substantial and the translational value of porcine sepsis models ...
    • 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), ...