Normothermic Machine Perfusion Reconstitutes Porcine Kidney Tissue Metabolism But Induces an Inflammatory Response, Which Is Reduced by Complement C5 Inhibition.

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.

Activation of the Innate Immune System in Brain-Dead Donors Can Be Reduced by Luminal Intestinal Preservation During Organ Procurement Surgery - A Porcine Model.

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.

The function of the complement system remains fully intact throughout the course of allogeneic stem cell transplantation.

Introduction: Hematopoietic stem cell transplantation (HSCT) is associated with immune complications and endothelial dysfunction due to intricate donor-recipient interactions, conditioning regimens, and inflammatory responses.

Methods: This study investigated the role of the complement system during HSCT and its interaction with the cytokine network. Seventeen acute myeloid leukemia patients undergoing HSCT were monitored, including blood sampling from the start of the conditioning regimen until four weeks post-transplant.

Escalated complement activation during hospitalization is associated with higher risk of 60-day mortality in SARS-CoV-2-infected patients.

Background: The complement system, an upstream recognition system of innate immunity, is activated upon SARS-CoV-2 infection. To gain a deeper understanding of the extent and duration of this activation, we investigated complement activation profiles during the acute phase of COVID-19, its persistence post-recovery and dynamic changes in relation to disease severity.

Methods: Serial blood samples were obtained from two cohorts of hospitalized COVID-19 patients (n = 457).

A novel selective leukocyte depletion human whole blood model reveals the specific roles of monocytes and granulocytes in the cytokine response to Escherichia coli.

The lepirudin-based human whole blood model is a well-established ex vivo system to characterize inflammatory responses. However, the contribution of individual cell populations to cytokine release has not been investigated. Thus, we modified the model by selectively removing leukocyte subpopulations to elucidate their contribution to the inflammatory response.

Effect of Intraperitoneal Radium-Labelled Microparticles on Compartmentalized Inflammation After Cytoreductive Surgery and Hypertherm Intraperitoneal Chemotherapy.

Despite extensive treatment with surgery and chemotherapy many patients with peritoneal metastases from colorectal cancer experience intraperitoneal disease relapse. The α-emitting radium-labelled microparticle radionuclide therapeutic Radspherin® is being explored as a novel treatment option for these patients. Radspherin® is specially designed to give local radiation to the surface of the peritoneal cavity and potentially kill remaining attached micrometastases as well as free-floating cancer cells, thus preventing future relapse.

Intracellular Complement Component 3 Attenuated Ischemia-Reperfusion Injury in the Isolated Buffer-Perfused Mouse Heart and Is Associated With Improved Metabolic Homeostasis.

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).

The Alternative Complement Pathway Is Activated Without a Corresponding Terminal Pathway Activation in Patients With Heart Failure.

Objective: Dysregulation of the complement system has been described in patients with heart failure (HF). However, data on the alternative pathway are scarce and it is unknown if levels of factor B (FB) and the C3 convertase C3bBbP are elevated in these patients. We hypothesized that plasma levels of FB and C3bBbP would be associated with disease severity and survival in patients with HF.

Complement ratios C3bc/C3 and sC5b-9/C5 do not increase the sensitivity of detecting acute complement activation systemically.

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.

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.

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.

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.

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.

Complement activation is associated with poor outcome after out-of-hospital cardiac arrest.

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.

Increased Local Inflammatory Response to MOC31PE Immunotoxin After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

Background: Despite extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), most patients with resectable peritoneal metastases from colorectal cancer experience disease relapse. MOC31PE immunotoxin is being explored as a novel treatment option for these patients. MOC31PE targets the cancer-associated epithelial cell adhesion molecule, and kills cancer cells by distinct mechanisms, simultaneously causing immune activation by induction of immunogenic cell death (ICD).

Rapid systemic surge of IL-33 after severe human trauma: a prospective observational study.

Background: Alarmins are considered proximal mediators of the immune response after tissue injury. Understanding their biology could pave the way for development of new therapeutic targets and biomarkers in human disease, including multiple trauma. In this study we explored high-resolution concentration kinetics of the alarmin interleukin-33 (IL-33) early after human trauma.

Open chest and pericardium facilitate transpulmonary passage of venous air emboli.

Background: Transpulmonary passage of air emboli can lead to fatal brain- and myocardial infarctions. We studied whether pigs with open chest and pericardium had a greater transpulmonary passage of venous air emboli than pigs with closed thorax.

Methods: We allocated pigs with verified closed foramen ovale to venous air infusion with either open chest with sternotomy and opening of the pleura and pericardium (n = 8) or closed thorax (n = 16).

Increased interleukin-6 and macrophage chemoattractant protein-1 are associated with respiratory failure in COVID-19.

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.

Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients.

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.

Complement Activation in 22q11.2 Deletion Syndrome.

The 22q11.2 deletion syndrome (22q11.2 del), also known as DiGeorge syndrome, is a genetic disorder with an estimated incidence of 1:3000 to 1:6000 births.

Complement component C3 and the TLR co-receptor CD14 are not involved in angiotensin II induced cardiac remodelling.

Inflammation is centrally involved in the development of cardiac hypertrophy and the processes of remodelling. The complement system and Toll-like receptor (TLR) family, two upstream arms of the innate immune system, have previously been reported to be involved in cardiac remodelling. However, the role of complement component 3 (C3), TLR co-receptor CD14 and the synergy between them have not been addressed during pressure overload-induced cardiac remodelling.

Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome.

Background: Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors.

Ficolins do not alter host immune responses to lipopolysaccharide-induced inflammation in vivo.

Ficolins are a family of pattern recognition molecules that are capable of activating the lectin pathway of complement. A limited number of reports have demonstrated a protective role of ficolins in animal models of infection. In addition, an immune modulatory role of ficolins has been suggested.

Properdin binding to complement activating surfaces depends on initial C3b deposition.

Two functions have been assigned to properdin; stabilization of the alternative convertase, C3bBb, is well accepted, whereas the role of properdin as pattern recognition molecule is controversial. The presence of nonphysiological aggregates in purified properdin preparations and experimental models that do not allow discrimination between the initial binding of properdin and binding secondary to C3b deposition is a critical factor contributing to this controversy. In previous work, by inhibiting C3, we showed that properdin binding to zymosan and Escherichia coli is not a primary event, but rather is solely dependent on initial C3 deposition.