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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In septic patients, both systemic inflammation and splanchnic hypoperfusion may cause enterocyte damage. Catecholamines may exert additional detrimental effects on mesenteric blood flow in these patients, and thereby contribute to this damage. Enterocyte damage itself results in impairment of gut barrier function and consequent translocation of bacteria/toxins. This may contribute to multiple organ failure and death by sustaining or amplifying the systemic inflammatory response. The aim of the study was 2-fold: to investigate which factors contribute to enterocyte damage in septic patients, and to assess whether enterocyte damage is associated with a sustained or amplified systemic inflammatory response. ⋯ In patients with septic shock, norepinephrine use is associated with more enterocyte damage. Although enterocyte damage is associated with increased 28-day mortality, it is not associated with a sustained or amplified systemic inflammatory response.
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Skeletal muscles (∼50% of the body weight) are affected during acute and late sepsis and represent one sepsis associate organ dysfunction. Cell membrane changes have been proposed to result from a channelopathy of yet unknown cause associated with mitochondrial dysfunction and muscle atrophy. We hypothesize that the channelopathy might be explained at least in part by the expression of non-selective channels. ⋯ At day seven after CLP, skeletal myofibers were found to present de novo expression (immunofluorescence) of connexins 39, 43, and 45 and P2X7 receptor whereas pannexin1 did not show significant changes. These changes were associated with increased sarcolemma permeability (∼4 fold higher dye uptake assay), ∼25% elevated in intracellular free-Ca concentration (FURA-2), activation of protein degradation via ubiquitin proteasome pathway (Murf and Atrogin 1 reactivity), moderate reduction in oxygen consumption not explained by changes in levels of relevant respiratory proteins, ∼3 fold decreased mitochondrial membrane potential (MitoTracker Red CMXRos) and ∼4 fold increased mitochondrial superoxide production (MitoSox). Since connexin hemichannels and P2X7 receptors are permeable to ions and small molecules, it is likely that they are main protagonists in the channelopathy by reducing the electrochemical gradient across the cell membrane resulting in detrimental metabolic changes and muscular atrophy.
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Serum lactate levels are traditionally interpreted as a marker of tissue hypoxia and often used clinically as an indicator of severity and outcome of sepsis/septic shock. Interestingly, recent studies involving the effects of tumor-derived lactate suggest that lactate itself may have an immunosuppressive effect in its local environment. This finding adds to the recent advances in immunometabolism that shed light on the importance of metabolism and metabolic intermediates in the regulation of innate immune and inflammatory responses in sepsis. In this article, we summarize recent studies, showing that the activation of immune cells requires aerobic glycolytic metabolism and that lactate produced by aerobic glycolysis may play an immunosuppressive role in sepsis.
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Pulmonary microvascular leakage is one of the characteristics of blood-air barrier dysfunction in septic acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Fibroblast growth factor-inducible 14 (Fn14) exerts diverse functions under certain circumstances. However, the role of Fn14 on the integrity of pulmonary microvascular endothelial cells (PMVECs) during sepsis remains unknown. ⋯ In addition, the degree of lung fibrosis was ameliorated and the survival of CLP mice was improved significantly after Fn14 blockade. In conclusion, Fn14 on PMVECs plays an important role in the progress of septic ALI. Fn14 blockade may prove to be an innovative lung-protective strategy for the treatment of septic ALI.
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Identify predictors of cardiogenic etiology among emergency department (ED) patients with hypotension, and use these predictors to create a clinical tool to discern cardiogenic etiology of hypotension. ⋯ Clinical predictors offer reasonable ED screening sensitivity for cardiogenic hypotension, while demonstrating sufficient specificity to facilitate early cardiac interventions.