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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Objective: Extracellular purines such as adenosine triphosphate (ATP), uridine triphosphate (UTP), and uridine diphosphate (UDP) and the ATP degradation product adenosine are biologically active signaling molecules, which accumulate at sites of metabolic stress in sepsis. They have potent immunomodulatory effects by binding to and activating P1 or adenosine and P2 receptors on the surface of leukocytes. Here we assessed the levels of extracellular purines, their receptors, metabolic enzymes, and cellular transporters in leukocytes of septic patients. ⋯ Conclusion: Because CD39 degrades ATP to adenosine monophosphate (AMP), the lower ATP levels in septic individuals may be the result of increased CD39 expression. This increased degradation of ATP did not lead to increased adenosine levels, which may be explained by the decreased expression of CD73, which converts AMP to adenosine. Altogether, our results demonstrate differential regulation of components of the purinergic system in PBMCs during human sepsis.
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Severe burns are associated with massive tissue destruction and cell death where nucleus histones and other damage-associated molecular patterns are released into the circulation and contribute to the pathogenesis of multiple-organ dysfunction. Currently, there is limited information regarding the pathophysiology of extracellular histones after burns, and the mechanisms underlying histone-induced vascular injury are not fully understood. In this study, by comparing the blood samples from healthy donors and burn patients, we confirmed that burn injury promoted the release of extracellular histones into the circulation, evidenced by increased plasma levels of histones correlating with injury severity. ⋯ Functionally, in vivo administration of an anti-Clec2d antibody attenuated burn-induced plasma leakage across mesenteric microvessels. Consistently, Clec2d knockdown in endothelial cells partially inhibited histone-induced endothelial barrier dysfunction. Together, our data suggest that burn injury-induced increases in circulating histones contribute to microvascular leakage and endothelial barrier dysfunction via a mechanism involving the endothelial Clec2d receptor.
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Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. There is currently no simple immune-imbalance-driven indicator for patients with sepsis. Methods: This study was conducted in Peking Union Medical College Hospital. ⋯ In trend analysis, as the trend of D1-D3-D7 IL-6/LY# decreases, the morality rate is lower than increase or fluctuate group (42.1% vs. 58.3%, 37.9% vs. 43.8%, 37.5% vs. 38.5% in high, moderate, and low D1 IL-6/LY# group separately). Conclusion: IL-6/LY# examined on first day in intensive care unit can be used as an immune-imbalance alert to identify sepsis patients with higher risk of 28-day mortality. Decreasing trend of IL-6/LY# suggests a lower 28-day mortality rate of sepsis patients.
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Introduction: Hypertension is a prevalent condition in the United States and leads to an increased risk of developing various comorbidities. However, the impact of new-onset hypertension after severe burns on patient outcomes is not known. We posit that hypertension onset after severe burn is associated with increased risk of developing comorbidities and mortality. ⋯ Age grouping indicated an elevated risk of developing AKI, heart failure, acute MI, and death. Conclusion: New-onset hypertension diagnosis in severely burned patients is associated with acute kidney injury, heart failure, acute MI, and death. Overall, males, older patients, and those with a higher % TBSA burned are at a higher risk of developing these comorbidities.
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Escherichia coli and Staphylococcus aureus are two of the most common bacterial species responsible for sepsis. While it is observed that they have disparate clinical phenotypes, the signaling differences elicited by each bacteria that drive this variance remain unclear. Therefore, we used human whole blood exposed to heat-killed E. coli or S. aureus and measured the transcriptomic signatures. ⋯ Using Ingenuity Pathway Analysis, it was demonstrated that nuclear factor erythroid 2-related factor 2 signaling, a main transcription factor in antioxidant responses, was predominately upregulated in S. aureus exposed blood relative to E. coli. Furthermore, the use of pharmacologics that preferentially targeted the nuclear factor erythroid 2-related factor 2 pathway led to differential cytokine profiles depending on the type of bacterial exposure. These findings reveal significant inflammatory dysregulation between E. coli and S. aureus and provide insight into the targeting of unique pathways to curb bacteria-specific responses.