Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Sepsis remains a major cause of morbidity and mortality in most intensive care units. Protracted sepsis can evolve into a state of profound immunosuppression characterized by secondary infections, frequently with opportunistic-type pathogens. Immunoadjuvant therapy is currently being evaluated as a novel treatment for patients with sepsis. ⋯ In contrast, anti-PD-1 seemed to have a greater effect on major histocompatibility complex class II expression on splenic macrophages and dendritic cells than IL-7. Combined treatment with IL-7 and anti-PD-1 produced additive effects on CD28 expression, lymphocyte proliferation, and splenic secretion of interferon-γ. In conclusion, the present study shows differences in immunomodulatory actions between IL-7 and anti-PD-1 and provides a potential rationale for combining IL-7 and anti-PD-1 in the therapy of sepsis.
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This report aims to facilitate the implementation of the Three Rs (replacement, reduction, and refinement) in the use of animal models or procedures involving sepsis and septic shock, an area where there is the potential of high levels of suffering for animals. The emphasis is on refinement because this has the greatest potential for immediate implementation. Specific welfare issues are identified and discussed, and practical measures are proposed to reduce animal use and suffering as well as reducing experimental variability and increasing translatability. The report is based on discussions and submissions from a nonregulatory expert working group consisting of veterinarians, animal technologists, and scientists with expert knowledge relevant to the field.
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Observational Study
Endogenous Microparticles Drive the Pro-Inflammatory Host Immune Response in Severely Injured Trauma Patients.
Severe trauma affects the immune system, which in its turn is associated with poor outcome. The mediators driving the immune responses in trauma are largely unknown. The aim of this study was to investigate the role of endogenous microparticles (MPs) in mediating the immune response following severe trauma. ⋯ On admission, trauma patients have a reduced immune response toward endotoxin challenge, which is, at least in part, mediated by MPs, which circulate in low numbers and in early stages. Most MPs originate from platelets, which indicates that these cells may be the most important source of MPs involved in initiating an inflammatory host response after injury.
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Clinical Trial
Inflammation-Induced Increases in Plasma Endocan Levels Are Associated With Endothelial Dysfunction in Humans In Vivo.
Although endothelial dysfunction is central to the pathogenesis of sepsis, no specific and clinically applicable marker for endothelial dysfunction is currently available. Endocan, a proteoglycan excreted by endothelial cells in response to inflammatory cytokines, may serve as such a marker. Our objective was to investigate the kinetics of endocan and its relationship with inflammation-induced endothelial dysfunction during experimental human endotoxemia. ⋯ No correlation existed between plasma levels of ICAM or VCAM and the attenuation of the acetylcholine-induced vasodilatory response. Endocan levels are related to endothelial dysfunction in humans in vivo during systemic inflammation evoked by experimental endotoxemia. Therefore, this study suggests that endocan could be a novel marker of endothelial dysfunction in inflammatory conditions.
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Glycogen synthase kinase 3 (GSK-3) is a serine-threonine kinase discovered decades ago to have an important role in glycogen metabolism. Today, we know that this kinase is involved in the regulation of many cell functions, including insulin signaling, specification of cell fate during embryonic development, and the control of cell division and apoptosis. Insulin and TDZD-8 (4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione) are inhibitors of GSK-3β that have been shown to possess organ-protective effects in inflammatory-mediated organ injury models. ⋯ In the thermal injury model, TDZD-8 was administered at 5 mg/kg (i.v.) 5 min before induction of injury and significantly reduced multiple organ dysfunction markers (liver, neuromuscular, and lung). In the lung, TDZD-8 reduced the histological signs of tissue injury, inflammatory markers (cytokines), and neutrophil chemotaxis/infiltration; reduced GSK-3β, nuclear factor-κB, and Akt activation; reduced caspase-3 and metalloproteinase-9 activation. Our study provides a new insight on the beneficial effects of GSK-3β inhibition on systemic inflammation and further elucidates the mechanism and pathway crosstalks by which TDZD-8 reduces the multiple organ injury elicited by thermal injury.