Søren Erik Pischke

• Færden, Ida Høy; Bliksøen, Marte; Schjalm, Camilla; Pettersen, Kristin; Liavåg, Olav Magnus Ivar & Majeed, Waleed Mohammed [Show all 9 contributors for this article] (2026). Immune activation during liver machine perfusion is shaped by perfusate composition and is independent of the ischemic injury. Frontiers in Immunology. 17, p. 1–12. doi: 10.3389/fimmu.2026.1874888. Full text in Research Archive
• Hunter, James; Hosgood, Sarah; Moers, Cyril; Leuvenink, Henri; Rabelink, Ton J. & Ploeg, Rutger [Show all 50 contributors for this article] (2025). Improving outcomes in kidney transplantation through advances in donor organ perfusion. Nature Reviews Nephrology. ISSN 1759-5061. 21(12), p. 818–832. doi: 10.1038/s41581-025-00993-8. Full text in Research Archive
• Camera, Andrea; Islam, Tawhidul; Parvan, Reza; Pischke, Søren Erik; Silva, Gustavo Jose Justo Da & Stensløkken, Kåre-Olav (2025). Prognostic and diagnostic biomarkers in liver transplantation: A systematic review and meta-analysis. Liver transplantation. ISSN 1527-6465. 31(12), p. 1499–1510. doi: 10.1097/LVT.0000000000000666. Full text in Research Archive Show summary

  Liver transplantation (LT) is a therapeutic option for patients suffering from end-stage liver disease. Recent research has probed the prognostic significance of biomarkers to predict graft function and mortality post-transplant, yet few candidates are recommended in clinical practice. We employed a pipeline that integrates meta-analysis (PRISMA 2020), followed by Kaplan–Meier (KM)-based individual patient data (IPD) analysis, aiming to identify potential novel prognostic biomarker panels for LT recipients. Ovid Medline, Embase, and Cochrane databases were searched. Twenty-one prognostic and 8 diagnostic studies were eligible, pooling 34,922 patients. Single biomarkers sampled at an early stage (≤15 d after LT) were significantly associated with graft-related outcomes (HR/OR 0.95 [0.94–0.97]) but did not predict mortality (HR/OR 1.00 [0.97–1.04]) or composite outcomes (HR/OR 1.02 [0.98–1.07]). Biomarkers in combination (GGT/bilirubin ratio, ALT+AST or ALT+AST+bilirubin+INR) predicted composite outcomes (graft failure or mortality, aHR/aOR 4.37 [2.65–7.21]). Biomarkers assessed at late stage (>15) did not show association with mortality (HR/OR 1.02 [1.00–1.04]) or composite outcomes (HR/OR 1.00 [0.99–1.01]). KM-based IPD analysis showed that coagulation factor V combined with ALT predicted graft survival (HR 2.12 [1.44–3.12]), and coagulation factor V+insulin-like growth factor 1 stratified the risk of patient survival (HR 2.97 [1.79–4.91]). Therefore, we were able to compare various scoring systems in predicting graft-related outcomes and mortality following LT. Additionally, we identified novel combinations of biomarkers that exhibited prognostic value for LT patients. Finally, we demonstrate that combined analytical tools for assessing large clinical datasets effectively evaluate multi-modal markers for risk stratification of early and late outcomes for LT.

• Boer, Eline de; Strandmoe, Anne-Lise; Sokolova, Marina; Michelsen, Trond Melbye; Quach, Huy Quang & Chaban, Viktoriia [Show all 12 contributors for this article] (2025). Extracellular mitochondrial DNA activates complement and is associated with complement activation in patients with out-of-hospital cardiac arrest. Scientific Reports. 15(1). doi: 10.1038/s41598-025-24705-1. Full text in Research Archive Show summary

  Abstract Synthetic analogues of mitochondrial DNA (mtDNA) have been reported as potent complement system activators. This study investigated the impact of endogenous mtDNA on complement activation. mtDNA and nuclear DNA (nDNA) were extracted from human placental tissue and complement activation was determined using ELISA. When incubated in lepirudin-anticoagulated human blood and plasma, increasing concentrations of mtDNA, but not nDNA, resulted in dose- and time-dependent increases in C3bc, C3bBbP and soluble C5b-9 (sC5b-9). In a clinical context, mtDNA, nDNA, and complement levels of 55 resuscitated out-of-hospital cardiac arrest (OHCA) patients were determined using qPCR and ELISA. C3bc and sC5b-9 correlated significantly with mtDNA and nDNA in OHCA patients. We conclude that mtDNA, but not nDNA, triggers in vitro complement activation, which holds significance in a clinical context in OHCA patients. This novel mode of human complement activation might explain pathophysiological mechanisms of sterile inflammation and could be relevant for innovative therapeutic strategies.

• Færden, Ida Høy; Bliksøen, Marte; Liavåg, Olav Magnus Ivar; Hou, Jie; Majeed, Waleed Mohammed & Torp, May-Kristin [Show all 14 contributors for this article] (2025). Organ monitoring and identification of ischemic liver injury during ex situ porcine liver machine perfusion—A randomized controlled study. Liver transplantation. ISSN 1527-6465. 32(2), p. 153–165. doi: 10.1097/lvt.0000000000000752. Full text in Research Archive Show summary

  The global shortage of donor livers has led to an increased reliance on extended-criteria donor livers, including those from donors after circulatory death. Utilizing marginal livers necessitates distinguishing between injured but recoverable livers and those that are irreversibly damaged. Bile duct injury, prevalent in these grafts, poses significant risks, as ischemic injuries can be challenging to assess and may lead to recipient bile duct strictures and ultimately graft failure. This study aimed to identify objective measurements that enhance existing viability criteria and facilitate the diagnosis of ischemic injuries. We employed ex situ machine perfusion (MP) to monitor porcine livers subjected to standardized biliary injury (BileINJ), standardized global liver injury (GlobalINJ), and no injury (CTRL, total n=23). Using microdialysis catheters and pCO 2 sensors, we analyzed liver tissue, hilar plate, and bile duct, in addition to standard viability assessments, collecting data on 77 variables. Principal component analysis indicated distinct clustering of the GlobalINJ and partially the BileINJ group away from the CTRL group during MP. Feature extraction models highlighted microdialysate lactate, lactate/pyruvate ratio, glycerol, tissue pCO 2 , and blood gas hematocrit as critical indicators for classifying liver state. Histopathological evaluations confirmed group-specific liver and bile injuries. We identified unique metabolic patterns that differentiate ischemically injured from non-injured porcine livers and were able to distinguish liver and biliary injury. Real-time monitoring of livers using microdialysis and tissue pCO 2 during MP is feasible and clinically available. Measurements taken in the hilar plate show the ability to identify bile duct damage while not introducing measurement devices to the vulnerable bile duct itself. Our findings enable more objective and timely selection of transplantable livers and warrant further investigation in clinical studies.

• Wiger, Christine Wagle; Ranheim, Trine; Arnesen, Henriette; Vaage, Ingvar Jarle; Pischke, Soeren & Yndestad, Arne [Show all 8 contributors for this article] (2025). TLR4 Inhibition Attenuated LPS-Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and Cardiomyocytes. Immunity,Inflammation and Disease. 13(1). doi: 10.1002/iid3.70133. Full text in Research Archive Show summary

  Background Sepsis is associated with myocardial injury and early mortality. The innate immune receptor Toll-like receptor 4 (TLR4) can recognize pathogen-associated-molecular-patterns (PAMPs) and damage-associated molecular patterns (DAMPs); the latter are released during tissue injury. We hypothesized that TLR4 inhibition reduces proinflammatory signaling and cytokine release in: (1) LPS or Escherichia coli-treated isolated mouse heart; (2) LPS-treated mouse primary adult cardiomyocytes; and (3) the isolated heart during ischemia–reperfusion. Methods Isolated C57BL/6N male mouse hearts were perfused for 120 min, with either LPS, E. coli, with and without CLI-095 (TLR4 inhibitor). Primary adult mouse cardiomyocytes were treated with LPS or LPS + CLI-095. Isolated hearts, exposed to 35 min of global ischemia, were treated with either vehicle or CLI-095 during reperfusion. Infarct size was quantified by triphenyltetrazolium staining. Cytokine expression was analyzed with ELISA, western blot analysis, and qPCR. Results In isolated hearts, E. coli increased the expression of proinflammatory cytokines (IL-6 and CXCL2), which was not attenuated with TLR4 inhibition. TLR4 inhibition reduced expression (p = 0.004) and release of IL-6 (p < 0.0001) in LPS-exposed isolated hearts. LPS activated the nuclear-factor κ-light-chain-enhancer of activated B cells signaling pathway (NF-κB) in primary adult cardiomyocytes. Moreover, TLR4 inhibition reduced LPS-induced mRNA expression and release of IL-6 in primary adult cardiomyocytes. Isolated hearts treated with CLI-095 during reperfusion after ischemia (induced DAMPs release) showed reduced infarct size (39 ± 17% to 26 ± 8%, p = 0.034) and decreased IL-6 release (p = 0.006). Conclusion Inhibition of TLR4 reduced proinflammatory signaling and cytokine release in LPS-treated and ischemia–reperfused isolated mouse hearts and in primary adult murine cardiomyocytes.

• Heldal, Torbjørn Fossum; Åsberg, Anders; Ueland, Thor; Reisæter, Anna Varberg; Pischke, Soeren & Mollnes, Tom Eirik [Show all 11 contributors for this article] (2025). Systemic inflammation is an important risk factor and predictor of graft loss and mortality one year after kidney transplantation. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1529812. Full text in Research Archive
• Mollnes, Tom Eirik; Jager, Neeltina M.; Ottens, Petra J.; Schjalm, Camilla; Veldhuis, Zwanida J. & Leuvenink, Henri G. D. [Show all 7 contributors for this article] (2025). Inhibition of the complement component C5 and the Toll-like receptor molecule CD14 prevents systemic and local kidney inflammation in mice experiencing brain death. Scientific Reports. 15(1). doi: 10.1038/s41598-025-12071-x. Full text in Research Archive Show summary

  Brain death (BD) induces a systemic inflammation impairing donor organ quality. Complement and Toll-like receptors (TLRs), with the key co-receptor CD14 molecule, are key innate recognition immune systems. We hypothesized that dual inhibition of complement (C5) and TLRs (CD14) will prevent BD-mediated innate immune inflammation. BD was induced in mice either untreated, treated with a C5 inhibitor, a CD14 inhibitor, or both. Blood and kidneys were collected after three hours. Cytokines were analyzed using enzyme-immuno assays and qPCR. In plasma, a substantial increase in interleukin-6 (IL-6), KC (IL-8 analogue), IL-12, monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein MIP-1α, MIP-1β, eotaxin, RANTES and G-CSF (median 90-fold increase) were observed in BD animals compared to sham (all p < 0.01). In kidneys, BD substantially induced IL-6, KC, TNF, MCP-1, P-Selectin, and VCAM-1 (all p < 0.01). In plasma, C5 and CD14 inhibition, either single or in combination, virtually abolished all cytokines in the BD animals (> 90% for six cytokines and 70–90% for three) (all p < 0.01). In kidneys, the effect of inhibition was similar (> 90% for IL-6 and KC and 60–80% for TNF and MCP-1 (all p < 0.01). Single and combined inhibition of C5 and CD14 efficiently prevented BD-induced systemic inflammation and reduced local kidney inflammation in a mouse model.

• Weiss, Marc Gjern; Jong, Anne Marye de; Seegert, Helene; Moeslund, Niels; Maassen, Hanno & Schjalm, Camilla [Show all 14 contributors for this article] (2024). Activation of the Innate Immune System in Brain-Dead Donors Can Be Reduced by Luminal Intestinal Preservation During Organ Procurement Surgery - A Porcine Model. Transplant International. ISSN 0934-0874. 37:13569, p. 1–12. doi: 10.3389/ti.2024.13569. Full text in Research Archive Show summary

  Organs obtained from brain dead donors can have suboptimal outcomes. Activation of the innate immune system and translocation of intestinal bacteria could be causative. Thirty two pigs were assigned to control, brain death (BD), BD + luminal intestinal polyethylene glycol (PEG), and BD + luminal intestinal University of Wisconsin solution (UW) groups. Animals were observed for 360 min after BD before organ retrieval. 2,000 mL luminal intestinal preservation solution was instilled into the duodenum at the start of organ procurement. Repeated measurements of plasma C3a, Terminal Complement Complex (TCC), IL-8, TNF, and lipopolysaccharide binding protein were analysed by immunoassays. C3a was significantly higher in the BD groups compared to controls at 480 min after brain death. TCC was significantly higher in BD and BD + UW, but not BD + PEG, compared to controls at 480 min. TNF was significantly higher in the BD group compared to all other groups at 480 min. LPS binding protein increased following BD in all groups except BD + PEG, which at 480 min was significantly lower compared with all other groups. Brain death induced innate immune system activation was decrease

• Boer, Eline de; Sokolova, Marina; Jager, Neeltina M.; Schjalm, Camilla; Weiss, Marc G. & Liavåg, Olav Magnus Ivar [Show all 16 contributors for this article] (2024). Normothermic Machine Perfusion Reconstitutes Porcine Kidney Tissue Metabolism But Induces an Inflammatory Response, Which Is Reduced by Complement C5 Inhibition. Transplant International. ISSN 0934-0874. 37:13348, p. 1–13. doi: 10.3389/ti.2024.13348. Full text in Research Archive Show summary

  Normothermic machine perfusion (NMP) is a clinical strategy to reduce renal ischemia-reperfusion injury (IRI). Optimal NMP should restore metabolism and minimize IRI induced inflammatory responses. Microdialysis was used to evaluate renal metabolism. This study aimed to assess the effect of complement inhibition on NMP induced inflammatory responses. Twenty-two pig kidneys underwent 18 h of static cold storage (SCS) followed by 4 h of NMP using a closed-circuit system. Kidneys were randomized to receive a C5-inhibitor or placebo during SCS and NMP. Perfusion resulted in rapidly stabilized renal flow, low renal resistance, and urine production. During SCS, tissue microdialysate levels of glucose and pyruvate decreased significantly, whereas glycerol increased (p < 0.001). In the first hour of NMP, glucose and pyruvate increased while glycerol decreased (p < 0.001). After 4 h, all metabolites had returned to baseline. Inflammatory markers C3a, soluble C5b-9, TNF, IL-6, IL-1β, IL-8, and IL-10 increased significantly during NMP in perfusate and kidney tissue. C5-inhibition significantly decreased perfusate and urine soluble C5b-9 (p < 0.001; p = 0.002, respectively), and tissue IL-1β (p = 0.049), but did not alter other inflammatory markers. Microdialysis can accurately monitor the effect of NMP on renal metabolism. Closed-circuit NMP induces inflammation, which appeared partly complement-mediated. Targeting additional immune inhibitors should be the next step.

• Chaban, Viktoriia; Boer, Eline de; Ekholt, Karin; Vaage, Ingvar Jarle; Mollnes, Tom Eirik & Nilsson, Per [Show all 8 contributors for this article] (2023). Escherichia coli-induced inflammatory responses are temperature-dependent in human whole blood ex vivo. Molecular Immunology. ISSN 0161-5890. 157, p. 70–77. doi: 10.1016/j.molimm.2023.03.006. Full text in Research Archive Show summary

  Systemic inflammatory conditions are often associated with hypothermia or hyperthermia. Therapeutic hypothermia is used in post-cardiac arrest and some other acute diseases. There is a need for more knowledge concerning the effect of various temperatures on the acute inflammatory response. The complement system plays a crucial role in initiating the inflammatory response. We hypothesized that temperatures above and below the physiologic 37 °C affect complement activation and cytokine production ex vivo. Lepirudin-anticoagulated human whole blood from 10 healthy donors was incubated in the presence or absence of Escherichia coli at different temperatures (4 °C, 12 °C, 20 °C, 33 °C, 37 °C, 39 °C, and 41 °C). Complement activation was assessed by the terminal C5b-9 complement complex (TCC) and the alternative convertase C3bBbP using ELISA. Cytokines were measured using a 27-plex assay. Granulocyte and monocyte activation was evaluated by CD11b surface expression using flow cytometry. A consistent increase in complement activation was observed with rising temperature, reaching a maximum at 41 °C, both in the absence (C3bBbP p < 0.05) and presence (C3bBbP p < 0.05 and TCC p < 0.05) of E. coli. Temperature alone did not affect cytokine production, whereas incubation with E. coli significantly increased cytokine levels of IL-1β, IL-2, IL-6, IL-8, IFN-γ, and TNF at temperatures > 20 °C. Maximum increase occurred at 39 °C. However, a consistent decrease was observed at 41 °C, significant for IL-1β (p = 0.003). Granulocyte CD11b displayed the same temperature-dependent pattern as cytokines, with a corresponding increase in endothelial cell apoptosis and necrosis. Thus, blood temperature differentially determines the degree of complement activation and cytokine release.

• Rydenfelt, Kristina Elisabeth; Kjøsen, Gisle; Horneland, Rune; Ludviksen, Judith K; Jenssen, Trond & Line, Pål Dag [Show all 10 contributors for this article] (2023). Local Postoperative Graft Inflammation in Pancreas Transplant Patients With Early Graft Thrombosis. Transplantation direct. 10(1), p. E1567–E1567. doi: 10.1097/TXD.0000000000001567. Full text in Research Archive Show summary

  Background. Graft thrombosis is the main cause of early graft loss following pancreas transplantation, and is more frequent in pancreas transplant alone (PTA) compared with simultaneous pancreas-kidney (SPK) recipients. Ischemia-reperfusion injury during transplantation triggers a local thromboinflammatory response. We aimed to evaluate local graft inflammation and its potential association with early graft thrombosis. Methods. In this observational study, we monitored 67 pancreas-transplanted patients using microdialysis catheters placed on the pancreatic surface during the first postoperative week. We analyzed 6 cytokines, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-8, interferon gamma-induced protein 10 (IP-10), macrophage inflammatory protein 1β (MIP-1β), IL-10, and the complement activation product complement activation product 5a (C5a) in microdialysis fluid. We compared the dynamic courses between patients with pancreas graft thrombosis and patients without early complications (event-free) and between PTA and SPK recipients. Levels of the local inflammatory markers, and plasma markers C-reactive protein, pancreas amylase, and lipase were evaluated on the day of thrombosis diagnosis compared with the first week in event-free patients. Results. IL-10 and C5a were not detectable. Patients with no early complications (n = 34) demonstrated high IL-1ra, IL-6, IL-8, IP-10, and MIP-1β concentrations immediately after surgery, which decreased to steady low levels during the first 2 postoperative days (PODs). Patients with early graft thrombosis (n = 17) demonstrated elevated IL-6 (P = 0.003) concentrations from POD 1 and elevated IL-8 (P = 0.027) concentrations from POD 2 and throughout the first postoperative week compared with patients without complications. IL-6 (P < 0.001) and IL-8 (P = 0.003) were higher on the day of thrombosis diagnosis compared with patients without early complications. No differences between PTA (n = 35) and SPK (n = 32) recipients were detected. Conclusions. Local pancreas graft inflammation was increased in patients experiencing graft thrombosis, with elevated postoperative IL-6 and IL-8 concentrations, but did not differ between PTA and SPK recipients. Investigating the relationship between the local cytokine response and the formation of graft thrombosis warrants further research.

• Clarke, Gerard Janez; Skandsen, Toril; Zetterberg, Henrik; Follestad, Turid; Einarsen, Cathrine Elisabeth & Vik, Anne [Show all 10 contributors for this article] (2023). Longitudinal Associations Between Persistent Post-Concussion Symptoms and Blood Biomarkers of Inflammation and CNS-Injury After Mild Traumatic Brain Injury. Journal of Neurotrauma. ISSN 0897-7151. 41, p. 1–17. doi: 10.1089/neu.2023.0419. Full text in Research Archive Show summary

  The aim of our study was to investigate the biological underpinnings of persistent post-concussion symptoms (PPCS) at 3 months following mild traumatic brain injury (mTBI). Patients (n = 192, age 16–60 years) with mTBI, defined as Glasgow Coma Scale (GCS) score between 13 and 15, loss of consciousness (LOC) <30 min, and post-traumatic amnesia (PTA) <24 h were included. Blood samples were collected at admission (within 72 h), 2 weeks, and 3 months. Concentrations of blood biomarkers associated with central nervous system (CNS) damage (glial fibrillary acidic protein [GFAP], neurofilament light [NFL], and tau) and inflammation (interferon gamma [IFNγ], interleukin [IL]-8, eotaxin, macrophage inflammatory protein-1-beta [MIP]-1β, monocyte chemoattractant protein [MCP]-1, interferon-gamma-inducible protein [IP]-10, IL-17A, IL-9, tumor necrosis factor [TNF], basic fibroblast growth factor [FGF]-basic platelet-derived growth factor [PDGF], and IL-1 receptor antagonist [IL-1ra]) were obtained. Demographic and injury-related factors investigated were age, sex, GCS score, LOC, PTA duration, traumatic intracranial finding on magnetic resonance imaging (MRI; within 72 h), and extracranial injuries. Delta values, that is, time-point differences in biomarker concentrations between 2 weeks minus admission and 3 months minus admission, were also calculated. PPCS was assessed with the British Columbia Post-Concussion Symptom Inventory (BC-PSI). In single variable analyses, longer PTA duration and a higher proportion of intracranial findings on MRI were found in the PPCS group, but no single biomarker differentiated those with PPCS from those without. In multi-variable models, female sex, longer PTA duration, MRI findings, and lower GCS scores were associated with increased risk of PPCS. Inflammation markers, but not GFAP, NFL, or tau, were associated with PPCS. At admission, higher concentrations of IL-8 and IL-9 and lower concentrations of TNF, IL-17a, and MCP-1 were associated with greater likelihood of PPCS; at 2 weeks, higher IL-8 and lower IFNγ were associated with PPCS; at 3 months, higher PDGF was associated with PPCS. Higher delta values of PDGF, IL-17A, and FGF-basic at 2 weeks compared with admission, MCP-1 at 3 months compared with admission, and TNF at 2 weeks and 3 months compared with admission were associated with greater likelihood of PPCS. Higher IL-9 delta values at both time-point comparisons were negatively associated with PPCS. Discriminability of individual CNS-injury and inflammation biomarkers for PPCS was around chance level, whereas the optimal combination of biomarkers yielded areas under the curve (AUCs) between 0.62 and 0.73. We demonstrate a role of biological factors on PPCS, including both positive and negative effects of inflammation biomarkers that differed based on sampling time-point after mTBI. PPCS was associated more with acute inflammatory processes, rather than ongoing inflammation or CNS-injury biomarkers. However, the modest discriminative ability of the models suggests other factors are more important in the development of PPCS.

• Heldal, Torbjørn Fossum; Åsberg, Anders; Ueland, Thor; Reisæter, Anna Varberg; Pischke, Soeren & Mollnes, Tom Eirik [Show all 11 contributors for this article] (2023). Systemic inflammation early after kidney transplantation is associated with long-term graft loss: a cohort study. Frontiers in Immunology. 14. doi: 10.3389/fimmu.2023.1253991. Full text in Research Archive Show summary

  Background: Early graft loss following kidney transplantation is mainly a result of acute rejection or surgical complications, while long-term kidney allograft loss is more complex. We examined the association between systemic inflammation early after kidney transplantation and long-term graft loss, as well as correlations between systemic inflammation scores and inflammatory findings in biopsies 6 weeks and 1 year after kidney transplantation.<p> <p>Methods: We measured 21 inflammatory biomarkers 10 weeks after transplantation in 699 patients who were transplanted between 2009 and 2012 at Oslo University Hospital, Rikshospitalet, Norway. Low-grade inflammation was assessed with predefined inflammation scores based on specific biomarkers: one overall inflammation score and five pathway-specific scores. Surveillance or indication biopsies were performed in all patients 6 weeks after transplantation. The scores were tested in Cox regression models.<p> <p>Results: Median follow-up time was 9.1 years (interquartile range 7.6-10.7 years). During the study period, there were 84 (12.2%) death-censored graft losses. The overall inflammation score was associated with long-term kidney graft loss both when assessed as a continuous variable (hazard ratio 1.03, 95% CI 1.01-1.06, P = 0.005) and as a categorical variable (4th quartile: hazard ratio 3.19, 95% CI 1.43-7.10, P = 0.005). In the pathway-specific analyses, fibrogenesis activity and vascular inflammation stood out. The vascular inflammation score was associated with inflammation in biopsies 6 weeks and 1 year after transplantation, while the fibrinogenesis score was associated with interstitial fibrosis and tubular atrophy.<p> <p>Conclusion: In conclusion, a systemic inflammatory environment early after kidney transplantation was associated with biopsy-confirmed kidney graft pathology and long-term kidney graft loss. The systemic vascular inflammation score correlated with inflammatory findings in biopsies 6 weeks and 1 year after transplantation.

• Rydenfelt, Kristina Elisabeth; Kjøsen, Gisle; Horneland, Rune; Ludviksen, Judith K; Jenssen, Trond & Line, Pål Dag [Show all 10 contributors for this article] (2023). Thromboinflammatory response is increased in pancreas transplant alone versus simultaneous pancreas-kidney transplantation and early pancreas graft thrombosis is associated with complement activation. Frontiers in Immunology. 14. doi: 10.3389/fimmu.2023.1044444. Full text in Research Archive Show summary

  Background: Pancreas transplant alone (PTA) recipients are more affected by pancreas graft thrombosis, and graft loss compared to simultaneous pancreas-kidney (SPK) recipients. The pathophysiology is unknown, but an increased immune response has been suggested in the PTA recipients. In this observational study, we compared perioperative thromboinflammation between PTA (n=32) and SPK (n=35) recipients, and between PTA recipients with (n=14) versus without (n=18) early graft thrombosis. Methods: We measured C-reactive protein (CRP), plasma markers of activated coagulation and complement, and cytokines preoperatively and daily during the first postoperative week. Results: Preoperatively, coagulation and complement activation markers were comparable between PTA and SPK recipients, while cytokine concentrations were higher in SPK recipients (TNF, IL-8, IP-10, MCP-1, MIP-1α; all p<0.05). On the first postoperative day, PTA recipients had higher coagulation activation, measured as thrombin-antithrombin complex (TAT), than SPK recipients (p=0.008). In the first postoperative week, PTA recipients showed higher relative cytokine release (IL-6, IL-8, G-CSF, IP-10, MCP-1, and MIP-1α; all p<0.05) while SPK recipients showed higher absolute cytokine concentrations (TNF, IL-1ra, IL-8, MIP-1α, and IL-4; all p<0.05). PTA and SPK recipients showed similar terminal complement complex (TCC, sC5b-9) activation. On the first postoperative day, TCC (OR 1.2 [95% CI 1.0-1.5] for 0.1 CAU/ml increase, p=0.02) and CRP (OR 1.2 [95% CI 1.0-1.3] for 10 mg/L increase, p=0.04) were associated with an increased risk of early graft thrombosis. TCC was specific for graft thrombosis, while CRP increased with several complications. PTA recipients with compared to those without graft thrombosis had higher TCC pre- (p=0.04) and postoperatively (p=0.03). Conclusion: The relative increase in postoperative thromboinflammatory response was more pronounced in PTA recipients. Complement activation was associated with an increased risk of graft thrombosis. This study indicates that innate immune activation rather than elevated levels may affect early postoperative pancreas graft thrombosis. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT01957696, identifier NCT01957696

• Bakkehaug, Jens Petter; Kåsine, Trine; Romundstad, Luis Georg; Narum, Jon; Laake, Jon Henrik & Svalebjørg, Morten [Show all 12 contributors for this article] (2023). Ekstrakorporal membranoksygenering ved akutt lungesviktsyndrom hos covid-19-pasienter. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(2). doi: 10.4045/tidsskr.22.0545. Full text in Research Archive
• Maassen, Hanno; Venema, Leonie H.; Weiss, Marc G.; Huijink, Tobias M.; Hofker, H. Sijbrand & Keller, Anna K. [Show all 12 contributors for this article] (2023). H2S-Enriched Flush out Does Not Increase Donor Organ Quality in a Porcine Kidney Perfusion Model. Antioxidants. 12:749(3), p. 1–15. doi: 10.3390/antiox12030749. Full text in Research Archive Show summary

  Kidney extraction time has a detrimental effect on post-transplantation outcome. This study aims to improve the flush-out and potentially decrease ischemic injury by the addition of hydrogen sulphide (H2S) to the flush medium. Porcine kidneys (n = 22) were extracted during organ recovery surgery. Pigs underwent brain death induction or a Sham operation, resulting in four groups: donation after brain death (DBD) control, DBD H2S, non-DBD control, and non-DBD H2S. Directly after the abdominal flush, kidneys were extracted and flushed with or without H2S and stored for 13 h via static cold storage (SCS) +/− H2S before reperfusion on normothermic machine perfusion. Pro-inflammatory cytokines IL-1b and IL-8 were significantly lower in H2S treated DBD kidneys during NMP (p = 0.03). The non-DBD kidneys show superiority in renal function (creatinine clearance and FENa) compared to the DBD control group (p = 0.03 and p = 0.004). No differences were seen in perfusion parameters, injury markers and histological appearance. We found an overall trend of better renal function in the non-DBD kidneys compared to the DBD kidneys. The addition of H2S during the flush out and SCS resulted in a reduction in pro-inflammatory cytokines without affecting renal function or injury markers.

• Rydenfelt, Kristina Elisabeth; Strand-Amundsen, Runar James; Horneland, Rune; Hødnebø, Stina; Kjøsen, Gisle & Pischke, Soeren [Show all 8 contributors for this article] (2022). Microdialysis and CO<inf>2</inf> sensors detect pancreatic ischemia in a porcine model. PLOS ONE. 17(2). doi: 10.1371/journal.pone.0262848. Full text in Research Archive Show summary

  Background: Pancreatic transplantation is associated with a high rate of early postoperative graft thrombosis. If a thrombosis is detected in time, a potentially graft-saving intervention can be initiated. Current postoperative monitoring lacks tools for early detection of ischemia. The aim of this study was to investigate if microdialysis and tissue pCO2 sensors detect pancreatic ischemia and whether intraparenchymal and organ surface measurements are comparable. Methods: In 8 anaesthetized pigs, pairs of lactate monitoring microdialysis catheters and tissue pCO2 sensors were simultaneously inserted into the parenchyma and attached to the surface of the pancreas. Ischemia was induced by sequential arterial and venous occlusions of 45-minute duration, with two-hour reperfusion after each occlusion. Microdialysate was analyzed every 15 minutes. Tissue pCO2 was measured continuously. We investigated how surface and parenchymal measurements correlated and the capability of lactate and pCO2 to discriminate ischemic from non-ischemic periods. Results: Ischemia was successfully induced by arterial occlusion in 8 animals and by venous occlusion in 5. During all ischemic episodes, lactate increased with a fold change of 3.2–9.5 (range) in the parenchyma and 1.7–7.6 on the surface. Tissue pCO2 increased with a fold change of 1.6–3.5 in the parenchyma and 1.3–3.0 on the surface. Systemic lactate and pCO2 remained unchanged. The area under curve (AUC) for lactate was 0.97 (95% confidence interval (CI) 0.93–1.00) for parenchymal and 0.90 (0.83–0.97) for surface (p<0.001 for both). For pCO2 the AUC was 0.93 (0.89–0.96) for parenchymal and 0.85 (0.81–0.90) for surface (p<0.001 for both). The median correlation coefficients between parenchyma and surface were 0.90 (interquartile range (IQR) 0.77–0.95) for lactate and 0.93 (0.89–0.97) for pCO2. Conclusions: Local organ monitoring with microdialysis and tissue pCO2 sensors detect pancreatic ischemia with adequate correlation between surface and parenchymal measurements. Both techniques and locations seem feasible for further development of clinical pancreas monitoring.

• Jager, Neeltina M.; Venema, Leonie H.; Arykbaeva, Asel S.; Meter-Arkema, Anita H.; Ottens, Petra J. & Kooten, Cees van [Show all 10 contributors for this article] (2022). Complement Is Activated During Normothermic Machine Perfusion of Porcine and Human Discarded Kidneys. Frontiers in Immunology. 13:831371, p. 1–12. doi: 10.3389/fimmu.2022.831371. Full text in Research Archive Show summary

  Background: The gap between demand and supply of kidneys for transplantation necessitates the use of kidneys from extended criteria donors. Transplantation of these donor kidneys is associated with inferior results, reflected by an increased risk of delayed graft function. Inferior results might be explained by the higher immunogenicity of extended criteria donor kidneys. Normothermic machine perfusion (NMP) could be used as a platform to assess the quality and function of donor kidneys. In addition, it could be useful to evaluate and possibly alter the immunological response of donor kidneys. In this study, we first evaluated whether complement was activated during NMP of porcine and human discarded kidneys. Second, we examined the relationship between complement activation and pro-inflammatory cytokines during NMP. Third, we assessed the effect of complement activation on renal function and injury during NMP of porcine kidneys. Lastly, we examined local complement C3d deposition in human renal biopsies after NMP. Methods: NMP with a blood-based perfusion was performed with both porcine and discarded human kidneys for 4 and 6 h, respectively. Perfusate samples were taken every hour to assess complement activation, pro-inflammatory cytokines and renal function. Biopsies were taken to assess histological injury and complement deposition. Results: Complement activation products C3a, C3d, and soluble C5b-9 (sC5b-9) were found in perfusate samples taken during NMP of both porcine and human kidneys. In addition, complement perfusate levels positively correlated with the cytokine perfusate levels of IL-6, IL-8, and TNF during NMP of porcine kidneys. Porcine kidneys with high sC5b-9 perfusate levels had significantly lower creatinine clearance after 4 h of NMP. In line with these findings, high complement perfusate levels were seen during NMP of human discarded kidneys. In addition, kidneys retrieved from brain-dead donors had significantly higher complement perfusate levels during NMP than kidneys retrieved from donors after circulatory death. Conclusion: Normothermic kidney machine perfusion induces complement activation in porcine and human kidneys, which is associated with the release of pro-inflammatory cytokines and in porcine kidneys with lower creatinine clearance. Complement inhibition during NMP might be a promising strategy to reduce renal graft injury and improve graft function prior to transplantation.

• Boer, Eline de; Sokolova, Marina; Quach, Huy Quang; Adam, Karin Ekholt Mc; Götz, Maximilian P. & Chaban, Viktoriia [Show all 13 contributors for this article] (2022). Synthetic Oligodeoxynucleotide CpG Motifs Activate Human Complement through Their Backbone Structure and Induce Complement-Dependent Cytokine Release. Journal of Immunology. ISSN 0022-1767. 209(9), p. 1760–1767. doi: 10.4049/jimmunol.2101191. Full text in Research Archive Show summary

  Bacterial and mitochondrial DNA, sharing an evolutionary origin, act as danger-associated molecular patterns in infectious and sterile inflammation. They both contain immunomodulatory CpG motifs. Interactions between CpG motifs and the complement system are sparsely described, and mechanisms of complement activation by CpG remain unclear. Lepirudin-anticoagulated human whole blood and plasma were incubated with increasing concentrations of three classes of synthetic CpGs: CpG-A, -B, and -C oligodeoxynucleotides and their GpC sequence controls. Complement activation products were analyzed by immunoassays. Cytokine levels were determined via 27-plex beads-based immunoassay, and CpG interactions with individual complement proteins were evaluated using magnetic beads coated with CpG-B. In whole blood and plasma, CpG-B and CpG-C (p < 0.05 for both), but not CpG-A (p > 0.8 for all), led to time- and dose-dependent increase of soluble C5b-9, the alternative complement convertase C3bBbP, and the C3 cleavage product C3bc. GpC-A, -B, and -C changed soluble fluid-phase C5b-9, C3bBbP, and C3bc to the same extent as CpG-A, -B, and -C, indicating a DNA backbone–dependent effect. Dose-dependent CpG-B binding was found to C1q (r = 0.83; p = 0.006) and factor H (r = 0.93; p < 0.001). The stimulatory complement effect was partly preserved in C2-deficient plasma and completely preserved in MASP-2–deficient serum. CpG-B increased levels of IL-1β, IL-2, IL-6, IL-8, MCP-1, and TNF in whole blood, which were completely abolished by inhibition of C5 and C5aR1 (p < 0.05 for all). In conclusion, synthetic analogs of bacterial and mitochondrial DNA activate the complement system via the DNA backbone. We suggest that CpG-B interacts directly with classical and alternative pathway components, resulting in complement-C5aR1–dependent cytokine release.

• Hou, Jie; Liavåg, Olav Magnus Ivar; Færden, Ida Høy; Martinsen, Ørjan Grøttem; Tønnessen, Tor Inge & Line, Pål Dag [Show all 10 contributors for this article] (2022). Utilization of dielectric properties for assessment of liver ischemia-reperfusion injury in vivo and during machine perfusion. Scientific Reports. 12(1). doi: 10.1038/s41598-022-14817-3. Full text in Research Archive Show summary

  Abstract There is a shortage of donor livers and patients consequently die on waiting lists worldwide. Livers are discarded if they are clinically judged to have a high risk of non-function following transplantation. With the aim of extending the pool of available donor livers, we assessed the condition of porcine livers by monitoring the microwave dielectric properties. A total of 21 livers were divided into three groups: control with no injury (CON), biliary injury by hepatic artery occlusion (AHEP), and overall hepatic injury by static cold storage (SCS). All were monitored for four hours in vivo, followed by ex vivo plurithermic machine perfusion (PMP). Permittivity data was modeled with a two-pole Cole–Cole equation, and dielectric properties from one-hour intervals were analyzed during in vivo and normothermic machine perfusion (NMP). A clear increasing trend in the conductivity was observed in vivo in the AHEP livers compared to the control livers. After four hours of NMP, separations in the conductivity were observed between the three groups. Our results indicate that dielectric relaxation spectroscopy (DRS) can be used to detect and differentiate liver injuries, opening for a standardized and reliable point of evaluation for livers prior to transplantation.

• Johnson, Christina; Quach, Huy Quang; Lau, Corinna; Ekholt, Karin; Espevik, Terje & Woodruff, Trent M. [Show all 9 contributors for this article] (2022). Thrombin Differentially Modulates the Acute Inflammatory Response to Escherichia coli and Staphylococcus aureus in Human Whole Blood. Journal of Immunology. ISSN 0022-1767. 208(12), p. 2771–2778. doi: 10.4049/jimmunol.2101033. Full text in Research Archive Show summary

  Thrombin plays a central role in thromboinflammatory responses, but its activity is blocked in the common ex vivo human whole blood models, making an ex vivo study of thrombin effects on thromboinflammatory responses unfeasible. In this study, we exploited the anticoagulant peptide Gly-Pro-Arg-Pro (GPRP) that blocks fibrin polymerization to study the effects of thrombin on acute inflammation in response to Escherichia coli and Staphylococcus aureus. Human blood was anticoagulated with either GPRP or the thrombin inhibitor lepirudin and incubated with either E. coli or S. aureus for up to 4 h at 37°C. In GPRP-anticoagulated blood, there were spontaneous elevations in thrombin levels and platelet activation, which further increased in the presence of bacteria. Complement activation and the expression of activation markers on monocytes and granulocytes increased to the same extent in both blood models in response to bacteria. Most cytokines were not elevated in response to thrombin alone, but thrombin presence substantially and heterogeneously modulated several cytokines that increased in response to bacterial incubations. Bacterial-induced releases of IL-8, MIP-1α, and MIP-1β were potentiated in the thrombin-active GPRP model, whereas the levels of IP-10, TNF, IL-6, and IL-1β were elevated in the thrombin-inactive lepirudin model. Complement C5-blockade, combined with CD14 inhibition, reduced the overall cytokine release significantly, both in thrombin-active and thrombin-inactive models. Our data support that thrombin itself marginally induces leukocyte-dependent cytokine release in this isolated human whole blood but is a significant modulator of bacteria-induced inflammation by a differential effect on cytokine patterns.

• Heldal, Torbjørn Fossum; Åsberg, Anders; Ueland, Thor; Reisæter, Anna Varberg; Pischke, Søren Erik & Mollnes, Tom Eirik [Show all 10 contributors for this article] (2022). Inflammation in the early phase after kidney transplantation is associated with increased long-term all-cause mortality. American Journal of Transplantation. ISSN 1600-6135. 22, p. 2016–2027. doi: 10.1111/ajt.17047. Full text in Research Archive Show summary

  In the general population low-grade inflammation has been established as a risk factor for all-cause mortality. We hypothesized that an inflammatory milieu beyond the time of recovery from the surgical trauma could be associated with increased long-term mortality in kidney transplant recipients (KTRs). This cohort study included 1044 KTRs. Median follow-up time post-engraftment was 10.3 years. Inflammation was assessed 10 weeks after transplantation by different composite inflammation scores based on 21 biomarkers. We constructed an overall inflammation score and five pathway-specific inflammation scores (fibrogenesis, vascular inflammation, metabolic inflammation, growth/angiogenesis, leukocyte activation). Mortality was assessed with Cox regression models adjusted for traditional risk factors. A total of 312 (29.9%) patients died during the follow-up period. Hazard ratio (HR) for death was 4.71 (95% CI:2.85-7.81, p

• Torp, May-Kristin; Ranheim, Trine; Schjalm, Camilla; Hjorth, Marit; Heiestad, Christina Mathisen & Dalen, Knut Tomas [Show all 13 contributors for this article] (2022). Intracellular Complement Component 3 Attenuated Ischemia-Reperfusion Injury in the Isolated Buffer-Perfused Mouse Heart and Is Associated With Improved Metabolic Homeostasis. Frontiers in Immunology. 13. doi: 10.3389/fimmu.2022.870811. Full text in Research Archive Show summary

  The innate immune system is rapidly activated during myocardial infarction and blockade of extracellular complement system reduces infarct size. Intracellular complement, however, appears to be closely linked to metabolic pathways and its role in ischemia-reperfusion injury is unknown and may be different from complement activation in the circulation. The purpose of the present study was to investigate the role of intracellular complement in isolated, retrogradely buffer-perfused hearts and cardiac cells from adult male wild type mice (WT) and from adult male mice with knockout of complement component 3 (C3KO). Main findings: (i) Intracellular C3 protein was expressed in isolated cardiomyocytes and in whole hearts, (ii) after ischemia-reperfusion injury, C3KO hearts had larger infarct size (32 ± 9% in C3KO vs. 22 ± 7% in WT; p=0.008) and impaired post-ischemic relaxation compared to WT hearts, (iii) C3KO cardiomyocytes had lower basal oxidative respiration compared to WT cardiomyocytes, (iv) blocking mTOR decreased Akt phosphorylation in WT, but not in C3KO cardiomyocytes, (v) after ischemia, WT hearts had higher levels of ATP, but lower levels of both reduced and oxidized nicotinamide adenine dinucleotide (NADH and NAD+, respectively) compared to C3KO hearts. Conclusion: intracellular C3 protected the heart against ischemia-reperfusion injury, possibly due to its role in metabolic pathways important for energy production and cell survival.

• Chaban, Viktoriia; Nakstad, Espen R.; Stær-Jensen, Henrik; Schjalm, Camilla; Seljeflot, Ingebjørg & Vaage, Ingvar Jarle [Show all 12 contributors for this article] (2021). Complement activation is associated with poor outcome after out-of-hospital cardiac arrest. Resuscitation. ISSN 0300-9572. 166, p. 129–136. doi: 10.1016/j.resuscitation.2021.05.038. Full text in Research Archive Show summary

  Background Cardiopulmonary resuscitation after cardiac arrest initiates a whole-body ischemia-reperfusion injury, which may activate the innate immune system, including the complement system. We hypothesized that complement activation and subsequent release of soluble endothelial activation markers were associated with cerebral outcome including death. Methods Outcome was assessed at six months and defined by cerebral performance category scale (1−2; good outcome, 3−5; poor outcome including death) in 232 resuscitated out-of-hospital cardiac arrest patients. Plasma samples obtained at admission and day three were analysed for complement activation products C3bc, the soluble terminal complement complex (sC5b-9), and soluble CD14. Endothelial cell activation was measured by soluble markers syndecan-1, sE-selectin, thrombomodulin, and vascular cell adhesion molecule. Results Forty-nine percent of the patients had good outcome. C3bc and sC5b-9 were significantly higher at admission compared to day three (p < 0.001 for both) and in patients with poor compared to good outcome (p = 0.03 and p < 0.001, respectively). Unadjusted, higher sC5b-9 at admission was associated with poor outcome (odds ratio 1.08 (95% CI 1.01–1.14), p = 0.024). Adjusted, sC5b-9 was still associated with outcome, but the association became non-significant when time to return-of-spontaneous-circulation above 25 min was included as a covariate. Endothelial cell activation markers increased from admission to day three, but only sE-selectin and thrombomodulin were significantly higher in patients with poor versus good outcome (p = 0.004 and p = 0.03, respectively) and correlated to sCD14 and sC5b-9/C3bc, respectively. Conclusion Complement system activation, reflected by sC5b-9 at admission, leading to subsequent endothelial cell activation, was associated with poor outcome in out-of-hospital cardiac arrest patients.

• Witczak, Bartlomiej J; Pischke, Søren E.; Reisæter, Anna V.; Midtvedt, Karsten; Ludviksen, Judith K & Heldal, Kristian [Show all 10 contributors for this article] (2021). Elevated Terminal C5b-9 Complement Complex 10 Weeks Post Kidney Transplantation Was Associated With Reduced Long-Term Patient and Kidney Graft Survival. Frontiers in Immunology. 12. doi: 10.3389/fimmu.2021.738927. Full text in Research Archive Show summary

  Background: The major reason for graft loss is chronic tissue damage, as interstitial fibrosis and tubular atrophy (IF/TA), where complement activation may serve as a mediator. The association of complement activation in a stable phase early after kidney transplantation with long-term outcomes is unexplored. Methods: We examined plasma terminal C5b-9 complement complex (TCC) 10 weeks posttransplant in 900 patients receiving a kidney between 2007 and 2012. Clinical outcomes were assessed after a median observation time of 9.3 years [interquartile range (IQR) 7.5–10.6]. Results: Elevated TCC plasma values (≥0.7 CAU/ml) were present in 138 patients (15.3%) and associated with a lower 10-year patient survival rate (65.7% vs. 75.5%, P < 0.003). Similarly, 10-year graft survival was lower with elevated TCC; 56.9% vs. 67.3% (P < 0.002). Graft survival was also lower when censored for death; 81.5% vs. 87.3% (P = 0.04). In multivariable Cox analyses, impaired patient survival was significantly associated with elevated TCC [hazard ratio (HR) 1.40 (1.02–1.91), P = 0.04] along with male sex, recipient and donor age, smoking, diabetes, and overall survival more than 1 year in renal replacement therapy prior to engraftment. Likewise, elevated TCC was independently associated with graft loss [HR 1.40 (1.06–1.85), P = 0.02] along with the same covariates. Finally, elevated TCC was in addition independently associated with death-censored graft loss [HR 1.69 (1.06–2.71), P = 0.03] as were also HLA-DR mismatches and higher immunological risk. Conclusions: Early complement activation, assessed by plasma TCC, was associated with impaired long-term patient and graft survival.

• Thomas, Anub Mathew; Chaban, Viktoriia; Pischke, Soeren; Orrem, Hilde Lang; Bosnes, Vidar & Sunde, Kjetil [Show all 13 contributors for this article] (2021). Complement ratios C3bc/C3 and sC5b-9/C5 do not increase the sensitivity of detecting acute complement activation systemically. Molecular Immunology. ISSN 0161-5890. 141, p. 273–279. doi: 10.1016/j.molimm.2021.11.016. Full text in Research Archive Show summary

  Background Complement activation plays an important pathogenic role in numerous diseases. The ratio between an activation product and its parent protein is suggested to be more sensitive to detect complement activation than the activation product itself. In the present study we explored whether the ratio between the activation product and the parent protein for C3 (C3bc/C3) and for C5 (sC5b-9/C5) increased the sensitivity to detect complement activation in acute clinical settings compared to the activation product alone. Materials and methods Samples from patients with acute heart failure following ST-elevated myocardial infarction (STEMI) and from patients with out-of-hospital cardiac arrest (OHCA) were used. C3, C3bc and C5, sC5b-9 were analysed in 629 and 672 patient samples, respectively. Healthy controls (n = 20) served to determine reference cut-off values for activation products and ratios, defined as two SD above the mean. Results Increased C3bc/C3- and sC5b-9/C5 ratios were vastly dependent on C3bc and sC5b-9. Thus, 99.5 % and 98.1 % of the increased C3bc/C3- and sC5b-9/C5 ratios were solely dependent on increased C3bc and sC5b-9, respectively. Significantly decreased C3 and C5 caused increased ratios in only 3/600 (0.5 %) and 4/319 (1.3 %) samples, respectively. Strong correlations between C3bc and C3bc/C3-ratio and between sC5b-9 and sC5b-9/C5-ratio were found in the STEMI- (r = 0.926 and r = 0.786, respectively) and the OHCA-population (r = 0.908 and r = 0.843, respectively; p < 0.0001 for all). Importantly, sC5b-9 identified worse outcome groups better than sC5b-9/C5-ratio. Conclusion C3bc and sC5b-9 were sensitive markers of complement activation. The ratios of C3bc/C3 and sC5b-9/C5 did not improve detection of complement activation systemically.

• Nilsson, Per; Johnson, Christina; Quach, Huy Quang; Macpherson, Alex; Durrant, Oliver & Pischke, Soeren [Show all 15 contributors for this article] (2021). 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. Journal of Immunology. ISSN 0022-1767. 207(6), p. 1641–1651. doi: 10.4049/jimmunol.2001471. Full text in Research Archive Show summary

  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 targeting fibrin polymerization downstream of thrombin, allowing complete endogenous thrombin generation. GPRP dose-dependently inhibited coagulation but allowed for platelet activation in accordance with thrombin generation. Spontaneous and bacterial-induced complement activation by Escherichia coli and Staphylococcus aureus, analyzed at the level of C3 and C5, were similar in blood anticoagulated with GPRP and the thrombin inhibitor lepirudin. In the GPRP model, endogenous thrombin, even at supra-physiologic concentrations, did not cleave native C5, despite efficiently cleaving commercially sourced purified C5 protein, both in buffer and when added to C5-deficient serum. In normal serum, only exogenously added, commercially sourced C5 was cleaved, whereas the native plasma C5 remained intact. Crucially, affinity-purified C5, eluted under mild conditions using an MgCl2 solution, was not cleaved by thrombin. Acidification of plasma to pH ≤ 6.8 by hydrochloric or lactic acid induced a C5 antigenic change, nonreversible by pH neutralization, that permitted cleavage by thrombin. Circular dichroism on purified C5 confirmed the structural change during acidification. Thus, we propose that pH-induced conformational change allows thrombin-mediated cleavage of C5 and that, contrary to previous reports, thrombin does not cleave plasma C5 in its native form, suggesting that thrombin cleavage of C5 may be restricted to certain pathophysiological conditions.

• Pearse, Rupert M.; Ranieri, Marco; Abbott, Tom EF; Pakats, Mari-Liis; Piervincenzi, Edoardo & Patel, Akshaykumar [Show all 37 contributors for this article] (2021). Postoperative continuous positive airway pressure to prevent pneumonia, re-intubation, and death after major abdominal surgery (PRISM): a multicentre, open-label, randomised, phase 3 trial. The Lancet Respiratory Medicine. ISSN 2213-2600. 9(11), p. 1221–1230. doi: 10.1016/s2213-2600(21)00089-8. Full text in Research Archive
• Lindholm, Espen; Bergmann, Gisli Björn; Haugaa, Håkon; Labori, Knut Jørgen; Yaqub, Sheraz & Bjørnbeth, Bjørn Atle [Show all 11 contributors for this article] (2021). Early detection of anastomotic leakage after pancreatoduodenectomy with microdialysis catheters: an observational Study. HPB. ISSN 1365-182X. 24(6), p. 901–909. doi: 10.1016/j.hpb.2021.10.020. Full text in Research Archive Show summary

  Background Microdialysis catheters can detect focal inflammation and ischemia, and thereby have a potential for early detection of anastomotic leakages after pancreatoduodenectomy. The aim was to investigate whether microdialysis catheters placed near the pancreaticojejunostomy can detect leakage earlier than the current standard of care. Methods Thirty-five patients with a median age 69 years were included. Two microdialysis catheters were placed at the end of surgery; one at the pancreaticojejunostomy, and one at the hepaticojejunostomy. Concentrations of glucose, lactate, pyruvate, and glycerol were analyzed hourly in the microdialysate during the first 24 h, and every 2–4 h thereafter. Results Seven patients with postoperative pancreatic fistulae (POPF) had significantly higher glycerol levels (P < 0.01) in the microdialysate already in the first postoperative samples. Glycerol concentrations >400 μmol/L during the first 12 postoperative hours detected patients with POPF with a sensitivity of 100% and a specificity of 93% (P < 0.001). After 24 h, lactate and lactate-to-pyruvate ratio were significantly higher (P < 0.05) and glucose was significantly lower (P < 0.05) in patients with POPF. Conclusion High levels of glycerol in microdialysate was an early detector of POPF. The subsequent inflammation was detected as increase in lactate and lactate-to-pyruvate ratio and a decrease in glucose (NCT03627559).

• Kjøsen, Gisle; Rydenfelt, Kristina Elisabeth; Horneland, Rune; Aandahl, Einar Martin; Line, Pål Dag & Dorenberg, Eric Jürgen [Show all 15 contributors for this article] (2021). Early detection of complications in pancreas transplants by microdialysis catheters, an observational feasibility study. PLOS ONE. 16(3), p. 1–16. doi: 10.1371/journal.pone.0247615. Full text in Research Archive Show summary

  Background Despite advances in immunosuppression and surgical technique, pancreas transplantation is encumbered with a high rate of complication and graft losses. Particularly, venous graft thrombi occur relatively frequently and are rarely detected before the transplant is irreversibly damaged. Methods To detect complications early, when the grafts are potentially salvageable, we placed microdialysis catheters anteriorly and posteriorly to the graft in a cohort of 34 consecutive patients. Glucose, lactate, pyruvate, and glycerol were measured at the bedside every 1–2 hours. Results Nine patients with graft venous thrombosis had significant lactate and lactate–to-pyruvate-ratio increases without concomitant rise in blood glucose or clinical symptoms. The median lactate in these patients was significantly higher in both catheters compared to non-events (n = 15). Out of the nine thrombi, four grafts underwent successful angiographic extraction, one did not require intervention and four grafts were irreversibly damaged and explanted. Four patients with enteric anastomosis leakages had significantly higher glycerol measurements compared to non-events. As with the venous thrombi, lactate and lactate-to-pyruvate ratio were also increased in six patients with graft surrounding hematomas. Conclusions Bedside monitoring with microdialysis catheters is a promising surveillance modality of pancreatic grafts, but differentiating between the various pathologies proves challenging.

• Rognes, Ingrid Nygren; Pischke, Søren Erik; Ottestad, William; Røislien, Jo; Berg, Jens Petter & Johnson, Christina [Show all 8 contributors for this article] (2021). Increased complement activation 3 to 6 h after trauma is a predictor of prolonged mechanical ventilation and multiple organ dysfunction syndrome: a prospective observational study. Molecular medicine (Cambridge, Mass. Print). ISSN 1076-1551. 27(1), p. 1–13. doi: 10.1186/s10020-021-00286-3. Full text in Research Archive Show summary

  Background - Complement activation is a central mechanism in systemic inflammation and remote organ dysfunction following major trauma. Data on temporal changes of complement activation early after injury is largely missing. We aimed to describe in detail the kinetics of complement activation in individual trauma patients from admission to 10 days after injury, and the association with trauma characteristics and outcome. Methods - In a prospective cohort of 136 trauma patients, plasma samples obtained with high time resolution (admission, 2, 4, 6, 8 h, and thereafter daily) were assessed for terminal complement complex (TCC). We studied individual TCC concentration curves and calculated a summary measure to obtain the accumulated TCC response 3 to 6 h after injury (TCC-AUC3–6). Correlation analyses and multivariable linear regression analyses were used to explore associations between individual patients’ admission TCC, TCC-AUC3–6, daily TCC during the intensive care unit stay, trauma characteristics, and predefined outcome measures. Results - TCC concentration curves showed great variability in temporal shapes between individuals. However, the highest values were generally seen within the first 6 h after injury, before they subsided and remained elevated throughout the intensive care unit stay. Both admission TCC and TCC-AUC3–6 correlated positively with New Injury Severity Score (Spearman’s rho, p-value 0.31, 0.0003 and 0.21, 0.02) and negatively with admission Base Excess (− 0.21, 0.02 and − 0.30, 0.001). Multivariable analyses confirmed that deranged physiology was an important predictor of complement activation. For patients without major head injury, admission TCC and TCC-AUC3–6 were negatively associated with ventilator-free days. TCC-AUC3–6 outperformed admission TCC as a predictor of Sequential Organ Failure Assessment score at day 0 and 4. Conclusions - Complement activation 3 to 6 h after injury was a better predictor of prolonged mechanical ventilation and multiple organ dysfunction syndrome than admission TCC. Our data suggest that the greatest surge of complement activation is found within the first 6 h after injury, and we argue that this time period should be in focus in the design of future experimental studies and clinical trials using complement inhibitors.

• Medeiros, Pedro Miguel Coelho; Schjalm, Camilla; Christiansen, Dorte; Sokolova, Marina; Pischke, Soeren Erik & Würzner, Reinhard [Show all 8 contributors for this article] (2021). Vitamin C, Hydrocortisone, and the Combination Thereof Significantly Inhibited Two of Nine Inflammatory Markers Induced by Escherichia Coli But Not by Staphylococcus Aureus - When Incubated in Human Whole Blood. Shock. ISSN 1073-2322. 57(1), p. 72–80. doi: 10.1097/SHK.0000000000001834. Full text in Research Archive Show summary

  Vitamin C combined with hydrocortisone is increasingly being used to treat septic patients, even though this treatment regimen is based on questionable evidence. When used, a marked effect on key players of innate immunity would be expected, as sepsis is featured by a dysregulated immune response. Here, we explored the effect of vitamin C and hydrocortisone alone and combined, in an ex vivo human whole-blood model of Escherichia coli- or Staphylococcus aureus-induced inflammation. Inflammatory markers for activation of complement (terminal C5b-9 complement complex [TCC]), granulocytes (myeloperoxidase), platelets (β-thromboglobulin), cytokines (tumor necrosis factor [TNF], IL-1β, IL6, and IL-8), and leukocytes (CD11b and oxidative burst) were quantified, by enzyme-linked immunosorbent assay, multiplex technology, and flow cytometry. In E. coli- and S. aureus-stimulated whole blood, a broad dose-titration of vitamin C and hydrocortisone alone did not lead to dose–response effects for the central innate immune mediators TCC and IL-6. Hence, the clinically relevant doses were used further. Compared to the untreated control sample, two of the nine biomarkers induced by E. coli were reduced by hydrocortisone and/or vitamin C. TNF was reduced by hydrocortisone alone (19%, P = 0.01) and by the combination (31%, P = 0.01). The oxidative burst of monocytes and granulocytes was reduced for both drugs alone and their combination, (ranging 8–19%, P < 0.05). Using S. aureus, neither of the drugs, alone nor in combination, had any effects on the nine biomarkers. In conclusion, despite the limitation of the ex vivo model, the effect of vitamin C and hydrocortisone on bacteria-induced inflammatory response in human whole blood is limited and following the clinical data.

• Nieuwenhuijs-Moeke, Gertrude J.; Pischke, Soeren E.; Berger, Stefan; Sanders, Jan Stephan F; Pol, Robert A & Struys, Michel M. R. F. [Show all 8 contributors for this article] (2020). Ischemia and Reperfusion Injury in Kidney Transplantation: Relevant Mechanisms in Injury and Repair. Journal of Clinical Medicine. 9:253(1), p. 1–33. doi: 10.3390/jcm9010253. Full text in Research Archive
• Chaban, Viktoriia; Clarke, Gerard; Skandsen, Toril; Islam, Rakibul; Einarsen, Cathrine Elisabeth & Vik, Anne [Show all 10 contributors for this article] (2020). Systemic inflammation persists the first year after mild traumatic brain injury: Results from the Prospective Trondheim Mild Traumatic Brain Injury Study. Journal of Neurotrauma. ISSN 0897-7151. 37(19), p. 2120–2130. doi: 10.1089/neu.2019.6963. Full text in Research Archive Show summary

  Innate immune activation has been attributed a key role in traumatic brain injury (TBI) and successive morbidity. In mild TBI (mTBI), however, the extent and persistence of innate immune activation are unknown. We determined plasma cytokine level changes over 12 months after an mTBI in hospitalized and non-hospitalized patients compared with community controls; and examined their associations to injury-related and demographic variables at admission. Prospectively, 207 patients presenting to the emergency department (ED) or general practitioner with clinically confirmed mTBI and 82 matched community controls were included. Plasma samples were obtained at admission, after 2 weeks, 3 months, and 12 months. Cytokine levels were analysed with a 27-plex beads-based immunoassay. Brain magnetic resonance imaging (MRI) was performed on all participants. Twelve cytokines were reliably detected. Plasma levels of interferon gamma (IFN-c), interleukin 8 (IL-8), eotaxin, macrophage inflammatory protein-1-beta (MIP-1b), monocyte chemoattractant protein 1 (MCP-1), IL-17A, IL-9, tumor necrosis factor (TNF), and basic fibroblast growth factor (FGFbasic) were significantly increased at all time-points in patients compared with controls, whereas IFN-c-inducing protein 10 (IP-10), platelet-derived growth factor (PDGF), and IL-1ra were not. IL-17A and FGF-basic showed significant increases in patients from admission to follow-up at 3 months, and remained increased at 12 months compared with admission. Interestingly, MRI findings were negatively associated with four cytokines: eotaxin, MIP-1b, IL-9, and IP-10, whereas age was positively associated with nine cytokines: IL-8, eotaxin, MIP-1b, MCP-1, IL-17A, IL-9, TNF, FGFbasic, and IL-1ra. TNF was also increased in those with presence of other injuries. In conclusion, mTBI activated the innate immune system consistently and this is the first study to show that several inflammatory cytokines remain increased for up to 1 year post-injury.

• Jørgensen, Marthe Jøntvedt; Holter, Jan Cato; Christensen, Erik; Schjalm, Camilla; Tonby, Kristian & Pischke, Soeren [Show all 22 contributors for this article] (2020). Increased interleukin-6 and macrophage chemoattractant protein-1 are associated with respiratory failure in COVID-19. Scientific Reports. 10. doi: 10.1038/s41598-020-78710-7. Full text in Research Archive Show summary

  In SARS-CoV-2 infection there is an urgent need to identify patients that will progress to severe COVID-19 and may benefit from targeted treatment. In this study we analyzed plasma cytokines in COVID-19 patients and investigated their association with respiratory failure (RF) and treatment in Intensive Care Unit (ICU). Hospitalized patients (n = 34) with confirmed COVID-19 were recruited into a prospective cohort study. Clinical data and blood samples were collected at inclusion and after 2–5 and 7–10 days. RF was defined as PaO2/FiO2 ratio (P/F) < 40 kPa. Plasma cytokines were analyzed by a Human Cytokine 27-plex assay. COVID-19 patients with RF and/or treated in ICU showed overall increased systemic cytokine levels. Plasma IL-6, IL-8, G-CSF, MCP-1, MIP-1α levels were negatively correlated with P/F, whereas combinations of IL-6, IP-10, IL-1ra and MCP-1 showed the best association with RF in ROC analysis (AUC 0.79–0.80, p < 0.05). During hospitalization the decline was most significant for IP-10 (p < 0.001). Elevated levels of pro-inflammatory cytokines were present in patients with severe COVID-19. IL-6 and MCP-1 were inversely correlated with P/F with the largest AUC in ROC analyses and should be further explored as biomarkers to identify patients at risk for severe RF and as targets for improved treatment strategies.

• Lipcsey, Miklos; Tenhunen, Jyrki; Pischke, Soeren; Kuitunen, Anne; Flaatten, Hans & Geer, Lina De [Show all 15 contributors for this article] (2020). Endotoxin removal in septic shock with the Alteco LPS Adsorber was safe but showed no benefit compared to placebo in the double-blind randomized controlled trial - the Asset Study. Shock. ISSN 1073-2322. 54(2), p. 224–231. doi: 10.1097/SHK.0000000000001503. Full text in Research Archive Show summary

  Purpose: Lipopolysaccharides (LPS) are presumed to contribute to the inflammatory response in sepsis. We investigated if extracorporeal Alteco LPS Adsorber for LPS removal in early gram-negative septic shock was feasible and safe. Also, effects on endotoxin level, inflammatory response, and organ function were assessed. Methods: A pilot, double-blinded, randomized, Phase IIa, feasibility clinical investigation was undertaken in six Scandinavian intensive care units aiming to allocate 32 septic shock patients with abdominal or urogenital focus on LPS Adsorber therapy or a Sham Adsorber, therapy without active LPS binding. The study treatment was initiated within 12 h of inclusion and given for 6 h daily on first 2 days. LPS was measured in all patients. Results: The investigation was terminated after 527 days with eight patients included in the LPS Adsorber group and seven in the Sham group. Twenty-one adverse effects, judged not to be related to the device, were reported in three patients in the LPS Adsorber group and two in the Sham group. Two patients in the Sham group and no patients in the LPS Adsorber group died within 28 days. Plasma LPS levels were low without groups differences during or after adsorber therapy. The changes in inflammatory markers and organ function were similar in the groups. Conclusions: In a small cohort of patients with presumed gram-negative septic shock, levels of circulating endotoxin were low and no adverse effects within 28 days after LPS adsorber-treatment were observed. No benefit compared with a sham device was seen when using a LPS adsorber in addition to standard care.

• Pischke, Soeren; Hødnebø, Stina; Wester, Torjus; Haugaa, Håkon; Kvernebo, Knut & Barratt-Due, Andreas [Show all 7 contributors for this article] (2020). Intraperitoneal microdialysis detects intestinal leakage earlier than hemodynamic surveillance and systemic inflammation in a pig model. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 56(2), p. 219–227. doi: 10.1080/00365521.2020.1863459. Full text in Research Archive Show summary

  Objective Anastomotic leakage is a common complication following large abdominal surgery, often developing to life-threatening abdominal sepsis due to late diagnosis. Currently, diagnostics rely on systemic hemodynamic and infection monitoring. We hypothesized that intraperitoneal microdialysis allows detection of peritonitis prior to changes in standard clinical parameters in a pig model. Materials and Methods We included six pigs; five underwent intraperitoneal fecal contamination, one had sham surgery for a total of 10 h. Microdialysis was established in four intraabdominal quadrants and two hepatic lobes. All pigs were hemodynamically monitored with pulmonary artery and femoral artery catheters. Blood samples were assessed for inflammatory markers, terminal complement complex (TCC), interleukin (IL)-6, IL-10, and plasminogen activator inhibitor-1 (PAI-1). Results Microdialysis showed intraperitoneal lactate increase during the first two hours after fecal contamination, which remained elevated throughout the observation time with concurrent decrease of glucose. Arterial lactate remained within reference range (<1,6mM). Systemic inflammatory markers TCC, IL-6, IL-10 and PAI-1 increased significantly after minimum four hours. Mean arterial pressure, stroke volume variation and cardiac output were not compromised the first five hours. Sham surgery did not influence any of the parameters. Conclusion Intraperitoneal fecal contamination leads to a rapid and pronounced intraperitoneal increase in lactate, decrease in glucose while pyruvate and glycerol levels remain unchanged. This distinct metabolic pattern of peritoneal inflammation can be easily detected by microdialysis. Observation of this pattern may minimize time to safe diagnosis of intestinal perforations after intraperitoneal fecal contamination.

• Ueland, Thor; Heggelund, Lars; Lind, Andreas; Holten, Aleksander Rygh; Tonby, Kristian & Michelsen, Annika [Show all 26 contributors for this article] (2020). Elevated plasma sTIM-3 levels in patients with severe COVID-19. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. 147(1), p. 92–98. doi: 10.1016/j.jaci.2020.09.007. Full text in Research Archive Show summary

  Background The pathogenesis of coronavirus disease 2019 (COVID-19) is still incompletely understood, but it seems to involve immune activation and immune dysregulation. Objective We examined the parameters of activation of different leukocyte subsets in COVID-19–infected patients in relation to disease severity. Methods We analyzed plasma levels of myeloperoxidase (a marker of neutrophil activation), soluble (s) CD25 (sCD25) and soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) (markers of T-cell activation and exhaustion), and sCD14 and sCD163 (markers of monocyte/macrophage activation) in 39 COVID-19–infected patients at hospital admission and 2 additional times during the first 10 days in relation to their need for intensive care unit (ICU) treatment. Results Our major findings were as follows: (1) severe clinical outcome (ICU treatment) was associated with high plasma levels of sTIM-3 and myeloperoxidase, suggesting activated and potentially exhausted T cells and activated neutrophils, respectively; (2) in contrast, sCD14 and sCD163 showed no association with need for ICU treatment; and (3) levels of sCD25, sTIM-3, and myeloperoxidase were inversely correlated with degree of respiratory failure, as assessed by the ratio of Pao2 to fraction of inspired oxygen, and were positively correlated with the cardiac marker N-terminal pro-B–type natriuretic peptide. Conclusion Our findings suggest that neutrophil activation and, in particular, activated T cells may play an important role in the pathogenesis of COVID-19 infection, suggesting that T-cell–targeted treatment options and downregulation of neutrophil activation could be of importance in this disorder.

• Holter, Jan Cato; Pischke, Soeren; Boer, Eline de; Lind, Andreas; Jenum, Synne & Holten, Aleksander Rygh [Show all 32 contributors for this article] (2020). Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 117(40), p. 25018–25025. doi: 10.1073/pnas.2010540117. Full text in Research Archive Show summary

  Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO2/FiO2 ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.

• Pischke, Søren; Hestenes, Siv Merete; Johansen, Harald Thidemann; Fure, Hilde; Bugge, Jan F & Espinoza, Andreas Westenvik [Show all 12 contributors for this article] (2019). Sepsis causes right ventricular myocardial inflammation independent of pulmonary hypertension in a porcine sepsis model. PLOS ONE. 14:e0218624(6). doi: 10.1371/journal.pone.0218624. Full text in Research Archive Show summary

  Introduction 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 therefore questioned. We hypothesized that porcine sepsis causes a myocardial inflammatory response which leads to myocardial dysfunction independent of PAH. Materials and methods Sepsis was induced by Escherichia coli-infusion in 10 pigs resulting in PAH and increased right ventricular pressure (RVP). The same degree of RVP was achieved by external pulmonary artery banding (PAB) in a consecutive series of 6 animals. Results Sepsis, but not PAB, led to increase in endothelial damage marker PAI-1 and cytokines TNF and IL-6 (all p<0.05) in plasma. In myocardium, TNF and IL-6 were significantly elevated in sepsis, TNF in both ventricles and IL-6 mostly in RV, while IL-1β, IL-18 and C5a were significantly higher in RV compared to LV after PAB (all p<0.05). Myocardial mRNA levels of IL-1β, IL-6, IL-18, IP-10, E-selectin and PAI-1 were significantly elevated in RV and LV during sepsis compared to PAB, while Caspase-1 was decreased in septic compared to PAB animals (all p<0.05). Cathepsin L activity was increased in RV by PAB, while sepsis inhibited this response. Escherichia coli-induced sepsis caused myocardial inflammation independent of PAH. Conclusion Prominent PAH should therefore not exclude porcine sepsis models to further our understanding of human sepsis.

• Thorgersen, Ebbe Billmann; Barratt-Due, Andreas; Haugaa, Håkon; Harboe, Morten; Pischke, Søren & Nilsson, Per [Show all 7 contributors for this article] (2019). The role of complement in liver injury, regeneration, and transplantation. Hepatology. ISSN 0270-9139. 70(2), p. 725–736. doi: 10.1002/hep.30508. Full text in Research Archive Show summary

  The liver is both an immunologically complex and a privileged organ. The innate immune system is a central player, in which the complement system emerges as a pivotal part of liver homeostasis, immune responses, and crosstalk with other effector systems in both innate and adaptive immunity. The liver produces the majority of the complement proteins and is the home of important immune cells such as Kupffer cells. Liver immune responses are delicately tuned between tolerance to many antigens flowing in from the alimentary tract, a tolerance that likely makes the liver less prone to rejection than other solid organ transplants, and reaction to local injury, systemic inflammation, and regeneration. Notably, complement is a double‐edged sword as activation is detrimental by inducing inflammatory tissue damage in, for example, ischemia–reperfusion injury and transplant rejection yet is beneficial for liver tissue regeneration. Therapeutic complement inhibition is rapidly developing for routine clinical treatment of several diseases. In the liver, targeted inhibition of damaged tissue may be a rational and promising approach to avoid further tissue destruction and simultaneously preserve beneficial effects of complement in areas of proliferation. Here, we argue that complement is a key system to manipulate in the liver in several clinical settings, including liver injury and regeneration after major surgery and preservation of the organ during transplantation.

• Ottestad, William Arne; Rognes, Ingrid Nygren; Pischke, Søren; Mollnes, Tom Eirik; Andersson, Ulf & Eken, Torsten (2019). Biphasic release of the alarmin high mobility group box 1 protein early after trauma predicts poor clinical outcome. Critical Care Medicine. ISSN 0090-3493. 47(8), p. e614–e622. doi: 10.1097/CCM.0000000000003800. Full text in Research Archive Show summary

  Objectives: The causal role of the prototype alarmin high mobility group box 1 protein in systemic inflammation and remote organ injury after trauma and shock is established in animal models but not in humans. Our aim was therefore to determine high mobility group box 1 protein concentration kinetics with high time resolution during the first hours after trauma in individual patients and investigate the association with outcome. Design: Prospective single-center observational study. Setting: University hospital Level I trauma center. Patients: Convenience recruitment of 136 trauma patients. Interventions: None. Measurements and Main Results: Total plasma high mobility group box 1 protein levels were analyzed with enzyme-linked immunosorbent assay in repeated samples. Relationships between predefined predictor variables and outcome were examined in multivariable linear regression models. Ventilator-free days was used as primary outcome measure. Two distinct high mobility group box 1 protein release phases were identified. An initial exponential decay phase with half-life 26 minutes was not correlated with outcome. In contrast, a second high mobility group box 1 protein wave peaking 3–6 hours after trauma in the most severely injured and physiologically deranged patients was consistently the most important predictor of outcome in our multivariable models, rendering all other predictor variables insignificant except for smaller contributions from age and sex, and of admission base excess for maximal creatinine concentration. Conclusions: High mobility group box 1 protein was released in two consecutive phases. Only the second high mobility group box 1 protein wave was a significant predictor of outcome. Patients with a high high mobility group box 1 protein concentration between 3 and 6 hours after trauma might hypothetically benefit from high mobility group box 1 protein-specific antagonist therapy.

• Orrem, Hilde Lang; Nilsson, Per; Pischke, Søren Erik; Kleveland, Ola; Yndestad, Arne & Ekholt, Karin [Show all 18 contributors for this article] (2018). IL-6 receptor inhibition by tocilizumab attenuated expression of C5a receptor 1 and 2 in non-ST-elevation myocardial infarction. Frontiers in Immunology. 9. doi: 10.3389/fimmu.2018.02035. Full text in Research Archive Show summary

  Background: Elevated interleukin-6 (IL-6) and complement activation are associated with detrimental effects of inflammation in coronary artery disease (CAD). The complement anaphylatoxins C5a and C3a interact with their receptors; the highly inflammatory C5aR1, and the C5aR2 and C3aR. We evaluated the effect of the IL-6 receptor (IL-6R)-antagonist tocilizumab on the expression of the anaphylatoxin receptors in whole blood from non-ST-elevation myocardial infarction (NSTEMI) patients. Separately, anaphylatoxin receptor expression in peripheral blood mononuclear cells (PBMC) from patients with different entities of CAD was investigated. Materials and Methods: NSTEMI patients were randomized to one dose of tocilizumab (n = 28) or placebo (n = 32) and observed for 6 months. Whole blood samples drawn at inclusion, at day 2, 3 and after 6 months were used for mRNA isolation. Plasma was prepared for analysis of complement activation measured as sC5b-9 by ELISA. Furthermore, patients with different CAD entities comprising stable angina pectoris (SAP, n = 22), non-ST-elevation acute coronary syndrome (NSTE-ACS, n = 21) and ST-elevation myocardial infarction (STEMI, n = 20) were included. PBMC was isolated from blood samples obtained at admission to hospital and mRNA isolated. Anaphylatoxin-receptor-expression was analyzed with qPCR using mRNA from whole blood and PBMC, respectively. Results: Our main findings were (i) Tocilizumab decreased C5aR1 and C5aR2 mRNA expression significantly (p < 0.001) and substantially (>50%) at day 2 and 3, whereas C3aR expression was unaffected. (ii) Tocilizumab did not affect complement activation. (iii) In analyzes of different CAD entities, C5aR1 expression was significantly increased in all CAD subgroups compared to controls with the highest level in the STEMI patients (p < 0.001). For C5aR2 and C3aR the expression compared to controls were more moderate with increased expression of C5aR2 in the STEMI group (p < 0.05) and C3aR in the NSTE-ACS group (p < 0.05). Conclusion: Expression of C5aR1 and C5aR2 in whole blood was significantly attenuated by IL-6R-inhibition in NSTEMI patients. These receptors were significantly upregulated in PBMC CAD patients with particularly high levels of C5aR1 in STEMI patients.

• Yang, Runkuan; Zhu, Shengtao; Pischke, Søren Erik; Haugaa, Håkon; Zou, Xiaoping & Tønnessen, Tor Inge (2018). Bile and circulating HMGB1 contributes to systemic inflammation in obstructive jaundice. Journal of Surgical Research. ISSN 0022-4804. 228, p. 14–19. doi: 10.1016/j.jss.2018.02.049. Full text in Research Archive
• Orrem, Hilde Lang; Nilsson, Per; Pischke, Søren Erik; Grindheim, Guro; Garred, Peter & Seljeflot, Ingebjørg [Show all 12 contributors for this article] (2018). Acute heart failure following myocardial infarction: complement activation correlates with the severity of heart failure in patients developing cardiogenic shock. ESC Heart Failure. 5(3), p. 292–301. doi: 10.1002/ehf2.12266. Full text in Research Archive Show summary

  Aims Heart failure (HF) is an impending complication to myocardial infarction. We hypothesized that the degree of complement activation reflects severity of HF following acute myocardial infarction. Methods and results The LEAF trial (LEvosimendan in Acute heart Failure following myocardial infarction) evaluating 61 patients developing HF within 48 h after percutaneous coronary intervention‐treated ST‐elevation myocardial infarction herein underwent a post hoc analysis. Blood samples were drawn from inclusion to Day 5 and at 42 day follow‐up, and biomarkers were measured with enzyme immunoassays. Regional myocardial contractility was measured by echocardiography as wall motion score index (WMSI). The cardiogenic shock group (n = 9) was compared with the non‐shock group (n = 52). Controls (n = 44) were age‐matched and sex‐matched healthy individuals. C4bc, C3bc, C3bBbP, and sC5b‐9 were elevated in patients at inclusion compared with controls (P < 0.01). The shock group had higher levels compared with the non‐shock group for all activation products except C3bBbP (P < 0.05). At Day 42, all products were higher in the shock group (P < 0.05). In the shock group, sC5b‐9 correlated significantly with WMSI at baseline (r = 0.68; P = 0.045) and at Day 42 (r = 0.84; P = 0.036). Peak sC5b‐9 level correlated strongly with WMSI at Day 42 (r = 0.98; P = 0.005). Circulating endothelial cell activation markers sICAM‐1 and sVCAM‐1 were higher in the shock group during the acute phase (P < 0.01), and their peak levels correlated with sC5b‐9 peak level in the whole HF population (r = 0.32; P = 0.014 and r = 0.30; P = 0.022, respectively). Conclusions Complement activation discriminated cardiogenic shock from non‐shock in acute ST‐elevation myocardial infarction complicated by HF and correlated with regional contractility and endothelial cell activation, suggesting a pathogenic role of complement in this condition.

• Pischke, Søren Erik; Gustavsen, Alice; Orrem, Hilde Lang; Egge, Kjetil Hagene; Courivaud, Fredric A A & Fontenelle, Hugues [Show all 15 contributors for this article] (2017). Complement factor 5 blockade reduces porcine myocardial infarction size and improves immediate cardiac function. Basic Research in Cardiology. ISSN 0300-8428. 112:20(3). doi: 10.1007/s00395-017-0610-9. Full text in Research Archive Show summary

  Inhibition of complement factor 5 (C5) reduced myocardial infarction in animal studies, while no benefit was found in clinical studies. Due to lack of cross-reactivity of clinically used C5 antibodies, different inhibitors were used in animal and clinical studies. Coversin (Ornithodoros moubata complement inhibitor, OmCI) blocks C5 cleavage and binds leukotriene B4 in humans and pigs. We hypothesized that inhibition of C5 before reperfusion will decrease infarct size and improve ventricular function in a porcine model of myocardial infarction. In pigs (Sus scrofa), the left anterior descending coronary artery was occluded (40 min) and reperfused (240 min). Coversin or placebo was infused 20 min after occlusion and throughout reperfusion in 16 blindly randomized pigs. Coversin significantly reduced myocardial infarction in the area at risk by 39% (p = 0.03, triphenyl tetrazolium chloride staining) and by 19% (p = 0.02) using magnetic resonance imaging. The methods correlated significantly (R = 0.92, p < 0.01). Tissue Doppler echocardiography showed increased systolic displacement (31%, p < 0.01) and increased systolic velocity (29%, p = 0.01) in coversin treated pigs. Interleukin-1β in myocardial microdialysis fluid was significantly reduced (31%, p < 0.05) and tissue E-selectin expression was significantly reduced (p = 0.01) in the non-infarcted area at risk by coversin treatment. Coversin ablated plasma C5 activation throughout the reperfusion period and decreased myocardial C5b-9 deposition, while neither plasma nor myocardial LTB4 were significantly reduced. Coversin substantially reduced the size of infarction, improved ventricular function, and attenuated interleukin-1β and E-selectin in this porcine model by inhibiting C5. We conclude that inhibition of C5 in myocardial infarction should be reconsidered.

• Barratt-Due, Andreas; Pischke, Søren Erik; Nilsson, Per; Espevik, Terje & Mollnes, Tom Eirik (2017). Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases-C3 or C5 emerge together with CD14 as promising targets. Journal of Leukocyte Biology. ISSN 0741-5400. 101(1), p. 193–204. doi: 10.1189/jlb.3VMR0316-132R. Full text in Research Archive Show summary

  The host is protected by pattern recognition systems, including complement and TLRs, which are closely cross-talking. If improperly activated, these systems might induce tissue damage and disease. Inhibition of single downstream proinflammatory cytokines, such as TNF, IL-1β, and IL-6, have failed in clinical sepsis trials, which might not be unexpected, given the substantial amounts of mediators involved in the pathogenesis of this condition. Instead, we have put forward a hypothesis of inhibition at the recognition phase by “dual blockade” of bottleneck molecules of complement and TLRs. By acting upstream and broadly, the dual blockade could be beneficial in conditions with improper or uncontrolled innate immune activation threatening the host. Key bottleneck molecules in these systems that could be targets for inhibition are the central complement molecules C3 and C5 and the important CD14 molecule, which is a coreceptor for several TLRs, including TLR4 and TLR2. This review summarizes current knowledge of inhibition of complement and TLRs alone and in combination, in both sterile and nonsterile inflammatory processes, where activation of these systems is of crucial importance for tissue damage and disease. Thus, dual blockade might provide a general, broad-acting therapeutic regimen against a number of diseases where innate immunity is improperly activated.

• Hellerud, Bernt C; Orrem, Hilde Lang; Dybwik, Knut Gustav; Pischke, Søren Erik; Barratt-Due, Andreas & Castellheim, Albert [Show all 15 contributors for this article] (2017). Combined inhibition of C5 and CD14 efficiently attenuated the inflammatory response in a porcine model of meningococcal sepsis. Journal of Intensive Care. ISSN 2052-0492. 5:21, p. 1–9. doi: 10.1186/s40560-017-0217-0. Full text in Research Archive Show summary

  Background 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. Methods Meningococcal sepsis was simulated by continuous intravenous infusion of an escalating dose of heat-inactivated Neisseria meningitidis administered over 3 h. The piglets were randomized, blinded to the investigators, to a positive control group (n = 12) receiving saline and to an interventional group (n = 12) receiving a recombinant anti-CD14 monoclonal antibody together with the C5 inhibitor coversin. Results A substantial increase in plasma complement activation in the untreated group was completely abolished in the treatment group (p = 0.006). The following inflammatory mediators were substantially reduced in plasma in the treatment group: Interferon-γ by 75% (p = 0.0001), tumor necrosis factor by 50% (p = 0.01), Interleukin (IL)-8 by 50% (p = 0.03), IL-10 by 40% (p = 0.04), IL-12p40 by 50% (p = 0.03), and granulocyte CD11b (CR3) expression by 20% (p = 0.01). Conclusion Inhibition of C5 and CD14 may be beneficial in attenuating the detrimental effects of complement activation and modulating the cytokine storm in patients with fulminant meningococcal sepsis.

• Gustavsen, Alice; Nymo, Stig Haugset; Landsem, Anne; Christiansen, Dorte; Ryan, Liv & Husebye, Harald [Show all 11 contributors for this article] (2016). 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. Journal of Infectious Diseases. ISSN 0022-1899. 214(1), p. 140–150. doi: 10.1093/infdis/jiw100. Full text in Research Archive Show summary

  Background. 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 bacteria-induced inflammatory response in human whole blood. Methods. Cytokines were measured by multiplex technology, and leukocyte activation markers CD11b and CD35 were measured by flow cytometry. Results. Lipopolysaccharide (LPS)–induced inflammatory markers were efficiently abolished by both anti-CD14 and eritoran. Anti-CD14 was significantly more effective than eritoran in inhibiting LPS-binding to HEK-293E cells transfected with CD14 and Escherichia coli–induced upregulation of monocyte activation markers (P < .01). Combining Cp40 with anti-CD14 was significantly more effective than combining Cp40 with eritoran in reducing E. coli–induced interleukin 6 (P < .05) and monocyte activation markers induced by both E. coli (P < .001) and Staphylococcus aureus (P < .01). Combining CP40 with anti-CD14 was more efficient than eritoran alone for 18 of 20 bacteria-induced inflammatory responses (mean P < .0001). Conclusions. Whole bacteria–induced inflammation was inhibited more efficiently by anti-CD14 than by eritoran, particularly when combined with complement inhibition. Combined CD14 and complement inhibition may prove a promising treatment strategy for bacterial sepsis

• Pischke, Søren Erik; Hyler, Stefan; Tronstad, Christian; Bergsland, Jacob; Fosse, Erik & Halvorsen, Per Steinar [Show all 8 contributors for this article] (2015). Myocardial tissue CO2 tension detects coronary blood flow reduction after coronary artery bypass in real-time. British Journal of Anaesthesia. ISSN 0007-0912. 114(3), p. 414–422. doi: 10.1093/bja/aeu381. Full text in Research Archive
• Egge, Kjetil Hagene; Thorgersen, Ebbe Billmann; Pischke, Søren Erik; Lindstad, Julie Katrine; Pharo, Anne Margrethe & Bongoni, Anjan K. [Show all 10 contributors for this article] (2015). Organ inflammation in porcine Escherichia coli sepsis is markedly attenuated by combined inhibition of C5 and CD14. Immunobiology. ISSN 0171-2985. 220(8), p. 999–1005. doi: 10.1016/j.imbio.2015.04.002. Full text in Research Archive
• Khan, Faraz Hameed; Pharo, Anne Margrethe; Lindstad, Julie Katrine; Mollnes, Tom Eirik; Tønnessen, Tor Inge & Pischke, Søren Erik (2015). Effect of Perfusion Fluids on Recovery of Inflammatory Mediators in Microdialysis. Scandinavian Journal of Immunology. ISSN 0300-9475. 82(5), p. 467–475. doi: 10.1111/sji.12332. Full text in Research Archive
• Hyler, Stefan; Pischke, Søren Erik; Halvorsen, Per Steinar; Espinoza, Andreas Westenvik; Bergsland, Jacob & Tønnessen, Tor Inge [Show all 8 contributors for this article] (2015). Continuous monitoring of regional function by a miniaturized ultrasound transducer allows early quantification of low-grade myocardial ischemia. Journal of the American Society of Echocardiography. ISSN 0894-7317. 28(4), p. 486–494. doi: 10.1016/j.echo.2014.12.014. Full text in Research Archive
• Fretland, Åsmund Avdem; Sokolov, Andrey; Postriganova, Nadezda; Kazaryan, Airazat M.; Pischke, Søren Erik & Nilsson, Per [Show all 11 contributors for this article] (2015). Inflammatory response after laparoscopic versus open resection of colorectal liver metastases: Data from the oslo-comet trial. Medicine. ISSN 0025-7974. 94:e1786(42). doi: 10.1097/MD.0000000000001786. Full text in Research Archive Show summary

  Laparoscopic and open liver resection have not been compared in randomized trials. The aim of the current study was to compare the inflammatory response after laparoscopic and open resection of colorectal liver metastases (CLM) in a randomized controlled trial. This was a predefined exploratory substudy within the Oslo CoMetstudy. Forty-five patients with CLM were randomized to laparoscopic (n ¼ 23) or open (n ¼ 22) resection. Ethylenediaminetetraacetic acidplasma samples were collected preoperatively and at defined time points during and after surgery and snap frozen at 80 o C. A total of 25 markers were examined using luminex and enzyme-linked immunosorbent assay techniques: high-mobility box group 1(HMGB-1), cellfree DNA (cfDNA), cytokines, and terminal C5b-9 complement complex complement activation. Eight inflammatory markers increased significantly from baseline: HMGB-1, cfDNA, interleukin (IL)-6, C-reactive protein, macrophage inflammatory protein -1b, monocyte chemotactic protein -1, IL-10, and terminal C5b-9 complement complex. Peak levels were reached at the end of or shortly after surgery. Five markers, HMGB-1, cfDNA, IL-6, Creactive protein, and macrophage inflammatory protein -1b, showed significantly higher levels in the open surgery group compared with the laparoscopic surgery group.

• Huber-Lang, Markus; Barratt-Due, Andreas; Pischke, Søren Erik; Sandanger, Øystein; Nilsson, Per & Nunn, Miles A. [Show all 10 contributors for this article] (2014). Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice. Journal of Immunology. ISSN 0022-1767. 192(11), p. 5324–5331. doi: 10.4049/jimmunol.1400341. Full text in Research Archive Show summary

  Sepsis and septic shock, caused by an excessive systemic host-inflammatory response, are associated with high morbidity and mortality. The complement system and TLRs provide important pattern recognition receptors initiating the cytokine storm by extensive cross-talk. We hypothesized that double blockade of complement C5 and the TLR coreceptor CD14 could improve survival of experimental polymicrobial sepsis. Mice undergoing cecal ligation and puncture (CLP)–induced sepsis were treated with neutralizing anti-CD14 Ab biG 53, complement C5 inhibitor coversin (Ornithodoros moubata C inhibitor), or a combination thereof. The inflammatory study (24-h observation) revealed statistically significant increases in 22 of 24 measured plasma biomarkers in the untreated CLP group, comprising 14 pro- and anti-inflammatory cytokines and 8 chemokines, growth factors, and granulocyte activation markers. Single CD14 or C5 blockade significantly inhibited 20 and 19 of the 22 biomarkers, respectively. Combined CD14 and C5 inhibition significantly reduced all 22 biomarkers (mean reduction 85%; range 54–95%) compared with the untreated CLP group. Double blockade was more potent than single treatment and was required to significantly inhibit IL-6 and CXCL1. Combined inhibition significantly reduced morbidity (motility and eyelid movement) and mortality measured over 10 d. In the positive control CLP group, median survival was 36 h (range 24–48 h). Combined treatment increased median survival to 96 h (range 24–240 h) (p = 0.001), whereas survival in the single-treatment groups was not significantly increased (median and range for anti-CD14 and anti-C5 treatment were 36 h [24–48 h] and 48 h [24–96 h]). Combined with standard intervention therapy, specific blockade of CD14 and C5 might represent a promising new therapeutic strategy for treatment of polymicrobial sepsis.

• Thorgersen, Ebbe Billmann; Pischke, Søren Erik; Barratt-Due, Andreas; Fure, Hilde; Lindstad, Julie Katrine & Pharo, Anne Margrethe [Show all 8 contributors for this article] (2013). Systemic CD14 inhibition attenuates organ inflammation in porcine escherichia coli sepsis. Infection and Immunity. ISSN 0019-9567. 81(9), p. 3173–3181. doi: 10.1128/IAI.00390-13. Full text in Research Archive
• Barratt-Due, Andreas; Sokolov, Andrey; Gustavsen, Alice; Hellerud, Bernt C; Egge, Kjetil Hagene & Pischke, Søren Erik [Show all 11 contributors for this article] (2013). Polyvalent immunoglobulin significantly attenuated the formation of IL-1 beta in Escherichia coli-induced sepsis in pigs. Immunobiology. ISSN 0171-2985. 218(5), p. 683–689. doi: 10.1016/j.imbio.2012.08.268. Full text in Research Archive
• Haugaa, Håkon; Almaas, Runar; Thorgersen, Ebbe Billmann; Foss, Aksel; Line, Pål Dag & Sanengen, Truls [Show all 13 contributors for this article] (2013). Clinical experience with microdialysis catheters in pediatric liver transplants. Liver transplantation. ISSN 1527-6465. 19(3), p. 305–314. doi: 10.1002/lt.23578. Full text in Research Archive
• Barratt-Due, Andreas; Thorgersen, Ebbe Billmann; Egge, Kjetil Hagene; Pischke, Søren Erik; Sokolov, Andrey & Hellerud, Bernt C [Show all 13 contributors for this article] (2013). Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis. Journal of Immunology. ISSN 0022-1767. 191(2), p. 819–827. doi: 10.4049/jimmunol.1201909. Full text in Research Archive
• Haugaa, Håkon; Thorgersen, Ebbe Billmann; Pharo, Anne Margrethe; Boberg, Kirsten Muri; Foss, Aksel & Line, Pål Dag [Show all 12 contributors for this article] (2012). Early bedside detection of ischemia and rejection in liver transplants by microdialysis. Liver transplantation. ISSN 1527-6465. 18(7), p. 839–849. doi: 10.1002/lt.23425. Full text in Research Archive
• Pischke, Søren Erik; Tronstad, Christian; Holhjem, Lars; Line, Pål Dag; Haugaa, Håkon & Tønnessen, Tor Inge (2012). Hepatic and Abdominal Carbon Dioxide Measurements Detect and Distinguish Hepatic Artery Occlusion and Portal Vein Occlusion in Pigs. Liver transplantation. ISSN 1527-6465. 18(12), p. 1485–1494. doi: 10.1002/lt.23544. Full text in Research Archive
• Barratt-Due, Andreas; Pischke, Søren Erik; Brekke, Ole Lars; Thorgersen, Ebbe Billmann; Nielsen, Erik Waage & Espevik, Terje [Show all 8 contributors for this article] (2012). Bride and groom in systemic inflammation - The bells ring for complement and Toll in cooperation. Immunobiology. ISSN 0171-2985. 217(11), p. 1047–1056. doi: 10.1016/j.imbio.2012.07.019. Full text in Research Archive
• Pischke, Søren Erik; Tronstad, Christian; Holhjem, Lars; Halvorsen, Per Steinar & Tønnessen, Tor Inge (2012). Perioperative detection of myocardial ischaemia/reperfusion with a novel tissue CO2 monitoring technology. European Journal of Cardio-Thoracic Surgery. ISSN 1010-7940. 42(1), p. 157–163. doi: 10.1093/ejcts/ezr278. Full text in Research Archive
• Haugaa, Håkon; Thorgersen, Ebbe Billmann; Pharo, Anne Margrethe; Boberg, Kirsten Muri; Foss, Aksel & Line, Pål Dag [Show all 13 contributors for this article] (2012). Inflammatory markers sampled by microdialysis catheters distinguish rejection from ischemia in liver grafts. Liver transplantation. ISSN 1527-6465. 18(12), p. 1421–1429. doi: 10.1002/lt.23503. Full text in Research Archive
• Tronstad, Christian; Pischke, Søren Erik; Holhjem, L; Tønnessen, Tor Inge; Martinsen, Ørjan Grøttem & Grimnes, Sverre (2010). Early detection of cardiac ischemia using a conductometric pCO(2) sensor: real-time drift correction and parameterization. Physiological Measurement. ISSN 0967-3334. 31(9), p. 1241–1255. doi: 10.1088/0967-3334/31/9/013. Full text in Research Archive

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• Clarke, Gerard Janez; Chaban, Viktoriia; Follestad, Turid; Vik, Anne; Einarsen, Cathrine Elisabeth & Zetterberg, Henrik [Show all 11 contributors for this article] (2023). Can Markers of Inflammation and CNS Injury Predict Post-concussion Syndrome at 3 months? Full text in Research Archive
• Laake, Jon Henrik; Aslam, Tayyba Naz; Barratt-Due, Andreas; Löwhagen, Bjørn; Pischke, Soeren & Tønnessen, Tor Inge [Show all 8 contributors for this article] (2023). ARDS eller akutt lungesviktsyndrom? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(10). doi: 10.4045/tidsskr.23.0402. Full text in Research Archive
• Clarke, Gerard Janez; Skandsen, Toril; Chaban, Viktoriia; Vik, Anne; Einarsen, Cathrine Elisabeth & Zetterberg, Henrik [Show all 10 contributors for this article] (2023). The Diagnostic Utility of Candidate Blood Biomarkers Reflecting Inflammation and CNS Injury for Determining Traumatic Intracranial Findings on CT/MRI following mild Traumatic Brain Injury. Full text in Research Archive
• Clarke, Gerard Janez; Skandsen, Toril; Zetterberg, Henrik; Einarsen, Cathrine Elisabeth; Vik, Anne & Mollnes, Tom Eirik [Show all 9 contributors for this article] (2023). Using Blood Biomarkers to Determine Intracranial Injury seen on CT/MRI following Mild Traumatic Brain Injury. Full text in Research Archive
• Laake, Jon Henrik; Astvad, Mads; Bentsen, Gunnar; Escher, Cecilia; Haney, Michael & Hoffmann-Petersen, Joachim [Show all 19 contributors for this article] (2022). A policy for diversity, equity, inclusion and anti-racism in the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI). Acta Anaesthesiologica Scandinavica. ISSN 0001-5172. 66(1), p. 141–144. doi: 10.1111/aas.13978. Full text in Research Archive
• Laake, Jon Henrik; Aasmundstad, Tor Aksel; Kåsine, Trine; Pischke, Soeren & Barratt-Due, Andreas (2020). Covid-19: Evidens-, eminens-, eller erfaringsbasert behandling? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(12), p. 1–2. doi: 10.4045/tidsskr.20.0649. Full text in Research Archive
• Sokolova, Marina; Ekholt, Karin; Mollnes, Tom Eirik & Pischke, Søren (2019). HYPOXIA FOLLOWED BY WHOLE BLOOD REOXYGENATIONINDUCED ENDOTHELIAL CELL ACTIVATION IN A COMPLEMENTC5 AND TOLL-LIKE RECEPTOR CD14 DEPENDENT MANNER. Full text in Research Archive
• Pischke, Søren Erik; Haugaa, Håkon & Haney, Michael (2017). A neglected organ in multiple organ failure - 'skin in the game'? Acta Anaesthesiologica Scandinavica. ISSN 0001-5172. 61(1), p. 5–7. doi: 10.1111/aas.12823. Full text in Research Archive
• Mollnes, Tom Eirik; Barratt-Due, Andreas; Pischke, Søren Erik; Sandanger, Inger; Nilsson, Per & Lambris, J [Show all 10 contributors for this article] (2013). Double-blockade of CD14 and complement component C5 abolish the inflammatory storm and improve survival in mouse polymicrobial sepsis. Molecular Immunology. ISSN 0161-5890. 56(3), p. 294–294. doi: 10.1016/j.molimm.2013.05.153. Full text in Research Archive
• Barratt-Duel, Andreas; Thorgersen, Ebbe Billmann; Egge, Kjetil Hagene; Pischke, Søren Erik; Sokolov, Andrey & Hellerud, Bernt C [Show all 11 contributors for this article] (2012). Combined inhibition of complement (C5) and CD14 markedly attenuates blood thrombogenicity, inflammation and hemodynamic changes in porcine sepsis. Immunobiology. ISSN 0171-2985. 217(11), p. 1152–1152. doi: 10.1016/j.imbio.2012.08.067. Full text in Research Archive
• Thorgersen, Ebbe Billmann; Pischke, Søren Erik; Barratt-Due, Andreas; Fure, Hilde; Lindstad, Julie Katrine & Pharo, Anne Margrethe [Show all 8 contributors for this article] (2012). Systemic CD14-inhibition attenuates local inflammatory responses organ-dependently in porcine Escherichia coli-sepsis. Immunobiology. ISSN 0171-2985. 217(11), p. 1206–1206. doi: 10.1016/j.imbio.2012.08.222. Full text in Research Archive
• Mollnes, Tom Eirik; Barratt-Due, Andreas; Pischke, Søren Erik; Sandanger, Øystein; Nunn, Miles A. & Espevik, Terje [Show all 8 contributors for this article] (2012). The systemic inflammatory reaction in polymicrobial sepsis induced by murine cecal ligation and puncture is equally dependent on C5 and CD14. Immunobiology. ISSN 0171-2985. 217(11), p. 1129–1129. doi: 10.1016/j.imbio.2012.08.002. Full text in Research Archive
• Hyler, Stefan; Pischke, Søren Erik; Halvorsen, Per Steinar; Espinoza, Andreas Westenvik; Hestenes, Siv Merete & Bergsland, Jacob [Show all 8 contributors for this article] (2010). Systolic and postsystolic velocities quantify low grade myocardial ischaemia by a miniaturized epicardial ultrasonic sensor. European Heart Journal. ISSN 0195-668X. 31, p. 45–45. Full text in Research Archive

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