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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Mitochondrial transplantation is a promising strategy for the treatment of several diseases. However, the effects of mitochondrial transplantation on the outcome of polymicrobial sepsis remain unclear. ⋯ These data displayed that mitochondrial replenishment reduces systemic inflammation and organ injury, enhances bacterial clearance, and improves the survival rate in sepsis. Thus, extraneous mitochondrial replenishment may be an effective adjunctive treatment to reduce sepsis-related mortality.
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Infection is a common and often deadly complication after burn injury. A major underlying factor is burn-induced immune dysfunction, particularly with respect to neutrophils as the primary responders to infection. Temporally after murine scald injury, we demonstrate impaired bone marrow neutrophil chemotaxis toward CXCL1 ex vivo. ⋯ A major signaling event upon CXCR2 activation is Akt phosphorylation and this was reduced when ceramide was elevated. In contrast, PTEN levels were elevated and PTEN-inhibition elevated phospho-Akt levels and mitigated the burn-induced neutrophil chemotaxis defect. Altogether, this study identifies a newly described pathway of ceramide-mediated suppression of neutrophil chemotaxis after burn injury and introduces potential targets to mitigate this defect and reduce infection-related morbidity and mortality after burn.
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Sepsis shifts cardiac metabolic fuel preference and this disruption may have implications for cardiovascular function. A greater understanding of the role of metabolism in the development and persistence of cardiovascular failure in sepsis could serve to identify novel pharmacotherapeutic approaches. ⋯ Among patients with septic shock, BCAA concentrations independently predict time to shock resolution. This study provides hypothesis generating data into the potential contribution of BCAAs to the pathophysiology of cardiovascular failure in sepsis, opening areas for future investigations.
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Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction associated with sepsis. The development of an effective strategy for early diagnosis and therapeutic intervention is essential for the prevention of poor prognosis of SAE. Translocator protein 18 kDa (TSPO) is a mitochondrial protein implicated in steroidogenesis and inflammatory responses. ⋯ Histological analysis revealed that ONO-2952 pretreatment suppressed the LPS-induced activation of TSPO-expressing microglia in the hippocampus of mice. Collectively, these results suggest that TSPO plays a critical role in the SAE mouse model. Based on this finding, monitoring TSPO activity, as well as the progress of endotoxemia and its sequelae in the animal model, would deepen our understanding of the underlying molecular mechanism of SAE.
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Hypoxia inducible factor 1 alpha (HIF-1α) is linked to the metabolic and immune alterations in septic patients. Stabilization of HIF-1α by hypoxia or inflammation promotes the expression of several genes related to glycolytic metabolism, angiogenesis, coagulation, cell proliferation, and apoptosis. Here, we analyzed public available blood transcriptome datasets from septic patients and evaluated by PCR array the expression of HIF-1α and other hypoxia responsive genes in peripheral blood mononuclear cells from patients with sepsis secondary to community acquired infections. ⋯ EGLN1, EGLN2, and HIF1AN, inhibitors of HIF-1α activation were downregulated in patients, regardless of the outcome, while HIF-1α and other target genes, such as PDK1 and HMOX1, expression were higher in non-survivors than in survivors, mainly at D7. Non-survivor patients also presented a higher SOFA score and lower PaO2/FiO2 ratio. Our results indicate a differential modulation of hypoxia pathway in leukocytes between septic patients who survived and those who did not survive with an increased intensity at D7, which is possibly influenced by disease severity and may affect the immune response in sepsis.