C1-esterase inhibitor attenuates the inflammatory response during human endotoxemia.

OBJECTIVE: Besides its role in regulation of the complement and contact system, C1-esterase inhibitor has other immunomodulating effects that could prove beneficial in patients with acute inflammation such as during sepsis or after trauma. We examined the immunomodulating properties of C1-esterase inhibitor during human experimental endotoxemia, in which the innate immune system is activated in the absence of activation of the classic complement pathway. DESIGN: Double-blind placebo-controlled study. SETTING: Research intensive care unit of the Radboud University Nijmegen Medical Centre. SUBJECTS: Twenty healthy volunteers. INTERVENTIONS: Intravenous injection of 2 ng/kg Escherichia coli lipopolysaccharide. Thirty minutes thereafter (to prevent binding of lipopolysaccharide), C1-esterase inhibitor concentrate (100 U/kg, n = 10) or placebo (n = 10) was infused. MEASUREMENTS AND MAIN RESULTS: Pro- and anti-inflammatory mediators, markers of endothelial and complement activation, hemodynamics, body temperature, and symptoms were measured. C1-esterase inhibitor reduced the release of proinflammatory cytokines as well as C-reactive protein (peak levels of: interleukin-6 1521 ± 209 vs. 932 ± 174 pg/mL [p = .04], tumor necrosis factor-α 1213 ± 187 vs. 827 ± 167 pg/mL [p = .10], monocyte chemotactic protein-1 6161 ± 1302 vs. 3373 ± 228 pg/mL [p = .03], interleukin-1ß 34 ± 5 vs. 23 ± 2 pg/mL [p < .01], C-reactive protein 39 ± 4 vs. 29 ± 2 mg/L [p = .02]). In contrast, release of the anti-inflammatory cytokine interleukin-10 was increased by C1-esterase inhibitor (peak level 73 ± 11 vs. 121 ± 18 pg/mL, p = .02). The increase in interleukin-1 receptor antagonist tended to be smaller in the C1-esterase inhibitor group, but this effect did not reach statistical significance (p = .07). Markers for endothelial activation were increased after lipopolysaccharide infusion, but no significant differences between groups were observed. The lipopolysaccharide-induced changes in heart rate, blood pressure, body temperature, and symptoms (all p < .001 over time) were not influenced by C1-esterase inhibitor. Complement fragment C4 was not increased after lipopolysaccharide challenge. CONCLUSIONS: This study is the first to demonstrate that C1-esterase inhibitor exerts anti-inflammatory effects in the absence of classic complement activation in humans.

A systematic review of randomized controlled trials exploring the effect of immunomodulative interventions on infection, organ failure, and mortality in trauma patients.

INTRODUCTION: Following trauma, patients may suffer an overwhelming pro-inflammatory response and immune paralysis resulting in infection and multiple organ failure (MOF). Various potentially immunomodulative interventions have been tested. The objective of this study is to systematically review the randomized controlled trials (RCTs) that investigate the effect of potentially immunomodulative interventions in comparison to a placebo or standard therapy on infection, MOF, and mortality in trauma patients. METHODS: A computerized search of MEDLINE, the Cochrane CENTRAL Register of Controlled Trials, and EMBASE yielded 502 studies, of which 18 unique RCTs were deemed relevant for this study. The methodological quality of these RCTs was assessed using a critical appraisal checklist for therapy articles from the Centre for Evidence Based Medicine. The effects of the test interventions on infection, MOF, and mortality rates and inflammatory parameters relative to the controls were recorded. RESULTS: In most studies, the inflammatory parameters differed significantly between the test and control groups. However, significant changes in infection, MOF, and mortality rates were only measured in studies testing immunoglobulin, IFN-γ, and glucan. CONCLUSIONS: Based on level 1b and 2b studies, administration of immunoglobulin, IFN-γ, or glucan have shown the most promising results to improve the outcome of trauma patients.

Postinjury immune monitoring: can multiple organ failure be predicted?

PURPOSE OF REVIEW: Multiple organ failure is the main cause of late morbidity and mortality after severe injury. This disease state is driven by a dysfunctional immune system. Prediction of multiple organ failure on the basis of clinical parameters appears to be insufficient. A better understanding of immunological pathogenesis underlying multiple organ failure may lead to better prediction and innovation in treatment strategy in order to increase the survival of trauma patients. RECENT FINDINGS: Immune monitoring has increased the knowledge of the pathogenesis of multiple organ failure, but many mechanisms underlying its cause and development remain to be elucidated. Consequently, adequate predictive markers for diagnosis and monitoring still need to be developed. SUMMARY: General markers of inflammation including cytokines are correlated with posttraumatic complications with a low sensitivity and specificity and are, therefore, of little use as prognostic markers. Current findings regarding the functionality of immune cells are promising and might be of prognostic value in the near future.

Myocardial blood supply by left ventricle-to-coronary artery channel: an old idea revisited.

Coronary artery disease is one of the most important causes of death in Western society. Attempts to revascularize the coronary artery by myocardial retroperfusion, direct revascularization from the left ventricle, and bypass surgery have finally led to percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) as standard treatment for coronary artery disease. Direct revascularization from the left ventricle has already been studied in the late 1960s, but the idea was rejected because of a decrease in flow in combination with a failure of myocardial function. Recently, a left ventricle-to-coronary artery (LV-CA) stent has renewed interest as an alternative procedure when PTCA and CABG are no option. Animal studies showed a change in flow pattern from diastolic coronary inflow at baseline to systolic coronary inflow followed by diastolic regurgitive flow during direct ventricular sourcing, resulting in a coronary flow of 50-75% of baseline flow. Global myocardial function decreased in the same extent as the coronary flow suggesting perfusion-contraction matching. In a recent pilot study in the anaesthetized pig, direct revascularization after acute proximal coronary ligation resulted in sufficient blood supply to the outer layers of the myocardium, however, in the inner layers a metabolic disbalance occurred. Incorporation of a valve-like mechanism to minimize the diastolic regurgitive flow may be necessary to improve the performance of the LV-CA stent. In addition, further research should be done in chronic ischemic animal models in which the effect of the collateral circulation on myocardial perfusion and performance is an important issue.

Homology in systemic neutrophil response induced by human experimental endotoxemia and by trauma.

The investigation of the trauma-induced innate immune responses is hampered by the wide variability in patients, type of trauma, and environmental factors. To circumvent this heterogeneity, we examined whether the systemic innate immune response toward human experimental endotoxemia is similar to the response during systemic inflammatory response syndrome after trauma. We tested the hypothesis that the innate immune response to pathogen-associated molecular pattern (e.g., lipopolysaccharides [LPSs]) and danger-associated molecular pattern (as induced by injury) leads to a comparable in vivo activation of human neutrophils. Escherichia coli LPS (2 ng/kg) was injected intravenously in nine healthy volunteers to induce a controlled systemic inflammatory response. Indices of systemic inflammation in this human inflammation model were compared with those of 12 trauma patients with a mean injury severity score of 19. Blood samples were withdrawn at 3 and 24 h after LPS-challenge or injury. Blood samples of nine healthy volunteers were used as control. Receptor expression was measured as readout for neutrophil activation by flow cytometry. Endotoxemia and injury resulted in a comparable activation phenotype of circulating neutrophils. This phenotype was characterized by downregulation of chemokine receptors CXCR1 and CXCR2 and of Fcγ receptors II and III. A significant difference between both conditions was seen in CD66b expression and for endotoxin resulted in an increased CD66b expression, whereas injury did not. Neutrophil activation was present 3 h after onset of inflammation, both during experimental endotoxemia as well as in trauma patients. Endotoxin and trauma appear to induce a similar neutrophil activation phenotype.

A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1.

Suppression of immune responses is necessary to limit damage to host tissue during inflammation, but it can be detrimental in specific immune responses, such as sepsis and antitumor immunity. Recently, immature myeloid cells have been implicated in the suppression of immune responses in mouse models of cancer, infectious disease, bone marrow transplantation, and autoimmune disease. Here, we report the identification of a subset of mature human neutrophils (CD11cbright/CD62Ldim/CD11bbright/CD16bright) as what we believe to be a unique circulating population of myeloid cells, capable of suppressing human T cell proliferation. These cells were observed in humans in vivo during acute systemic inflammation induced by endotoxin challenge or by severe injury. Local release of hydrogen peroxide from the neutrophils into the immunological synapse between the neutrophils and T cells mediated the suppression of T cell proliferation and required neutrophil expression of the integrin Mac-1 (αMß2). Our data demonstrate that suppression of T cell function can be accomplished by a subset of human neutrophils that can be systemically induced in response to acute inflammation. Identification of the pivotal role of neutrophil Mac-1 and ROS in this process provides a potential target for modulating immune responses in humans.

The effect of C1-esterase inhibitor on systemic inflammation in trauma patients with a femur fracture - The CAESAR study: study protocol for a randomized controlled trial.

BACKGROUND: Systemic inflammation in response to a femur fracture and the additional fixation is associated with inflammatory complications, such as acute respiratory distress syndrome and multiple organ dysfunction syndrome. The injury itself, but also the additional procedure of femoral fixation induces a release of pro-inflammatory cytokines such as interleukin-6. This results in an aggravation of the initial systemic inflammatory response, and can cause an increased risk for the development of inflammatory complications. Recent studies have shown that administration of the serum protein C1-esterase inhibitor can significantly reduce the release of circulating pro-inflammatory cytokines in response to acute systemic inflammation. OBJECTIVE: Attenuation of the surgery-induced additional systemic inflammatory response by perioperative treatment with C1-esterase inhibitor of trauma patients with a femur fracture. METHODS: The study is designed as a double-blind randomized placebo-controlled trial. Trauma patients with a femur fracture, Injury Severity Score ≥ 18 and age 18-80 years are included after obtaining informed consent. They are randomized for administration of 200 U/kg C1-esterase inhibitor intravenously or placebo (saline 0.9%) just before the start of the procedure of femoral fixation. The primary endpoint of the study is Δ interleukin-6, measured at t = 0, just before start of the femur fixation surgery and administration of C1-esterase inhibitor, and t = 6, 6 hours after administration of C1-esterase inhibitor and the femur fixation. CONCLUSION: This study intents to identify C1-esterase inhibitor as a safe and potent anti-inflammatory agent, that is capable of suppressing systemic inflammation in trauma patients. This might facilitate early total care procedures by lowering the risk of inflammation in response to the surgical intervention. This could result in increased functional outcomes and reduced health care related costs.