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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This study was conducted to reveal if the mitochondrial unfolded protein response (mtUPR), a conserved mitochondrial-nuclear communication mechanism, plays a critical role in the protein quality control system to cope with damaged protein during sepsis. Sepsis was induced by cecal ligation and puncture (CLP) in Sprague-Dawley rats. The efficiency of mtUPR was evaluated by measuring the transcriptional factors (CCAAT/enhancer-binder protein homologous protein [CHOP] and CCAAT/enhancer-binder protein-β) and chaperones (heat shock protein 60 [Hsp60] and Hsp10) expression in response to hepatic mitochondrial oxidized proteins (carbonylated proteins, car-proteins) and multi-ubiquitinated proteins (ub-proteins). ⋯ Interestingly, we evaluated the ratio of mitochondrial Hsp60/Hsp10 to the ub-proteins and found that both ratios were statistically lowered at the time points of 9 and 18 h in comparison with 3 and 6 h after CLP. These ratios were also significantly negatively correlated with glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase levels, suggesting that the ratios could act as an index of mtUPR failure and be a useful tool in estimating the ability of mitochondrial-nuclear communication in sepsis. In conclusion, the results indicated that mtUPR failure occurred during sepsis, and that the index of mtUPR may be a valuable measurement in assessing the severity of organ dysfunction in the clinical setting.
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The mechanism of immunosuppression induced by severe sepsis is not fully understood. The production of prostaglandin E2 (PGE2) during sepsis is well known, but its role in long-term consequences of sepsis has not been explored. The current study evaluates the role of PGE2 in the development of immunosuppression secondary to sepsis and its potential as therapeutic target. ⋯ Furthermore, sepsis also altered key enzymes in PGE2 synthesis and degradation. Our results indicate the involvement of PGE2 in severe sepsis-induced immunosuppression. Inhibition of PGE2 production represents an attractive target to improve innate immune response against secondary infection in the immunocompromised host.
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Blood transfusion is a well-established risk factor for adverse outcomes during sepsis. The specific mechanisms responsible for this effect remain elusive, and few studies have investigated this phenomenon in a model that reflects not only the clinical circumstances in which blood is transfused, but also how packed red blood cells (PRBCs) are created and stored. Using a cecal ligation and puncture model of polymicrobial sepsis as well as creating murine allogeneic and stored PRBCs in a manner that replicates the clinical process, we have demonstrated that transfusion of PRBCs induces numerous effects on leukocyte subpopulations. ⋯ Myeloid cells behaved similarly, although they were able to produce more reactive oxygen species. Overall, transfusion in the septic mouse may contribute to the persistent immune dysfunction known to be associated with this process, rather than simply promote proinflammatory or anti-inflammatory effects on the host. Thus, it is possible that blood transfusion contributes to the multiple known effects of sepsis on leukocyte populations that have been shown to result in increased morbidity and mortality.
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In sepsis, large quantities of inflammatory cytokines are released into the bloodstream. The cellular source of these cytokines is unclear, and we have here investigated to what extent circulating cells in blood contributed to this production. We used the enzyme-linked immunospot technique to study the spontaneous as well as the lipopolysaccharide (LPS)-induced secretion of the proinflammatory cytokines interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), granulocyte-macrophage colony-stimulating factor, IL-1β, IL-12p40, and the anti-inflammatory cytokine IL-10 from whole-blood cells. ⋯ The reduced number of cytokine-secreting cells in response to LPS stimulation correlated with disease severity, as expressed by Sequential Organ Failure Assessment score and the stage of sepsis. In summary, circulating leukocytes did not appear to be responsible for the increased plasma levels of cytokines observed in sepsis. A selective sepsis-induced downregulation of cytokine secretion in response to LPS underscores the complexity of cytokine regulation in sepsis.