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 is an enormous public health issue and the leading cause of death in critically ill patients in intensive care units. Overwhelming inflammation, characterized by cytokine storm, oxidative threats, and neutrophil sequestration, is an underlying component of sepsis-associated organ failure. Despite recent advances in sepsis research, there is still no effective treatment available beyond the standard of care and supportive therapy. ⋯ Although the detrimental role of ER stress during infections has been demonstrated, there is growing evidence that ER stress participates in the pathogenesis of sepsis. In this review, we summarize current research in the context of ER stress and UPR signaling associated with sepsis and its related clinical conditions, such as trauma-hemorrhage and ischemia/reperfusion injury. We also discuss the potential implications of ER stress as a novel therapeutic target and prognostic marker in patients with sepsis.
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Systemic inflammation is a well-known risk factor for respiratory muscle weakness. Studies using animal models of inflammation have shown that endotoxin administration induces diaphragm dysfunction. However, the effects of in vivo endotoxin administration on diaphragm function in humans have not been studied. Our aim was to evaluate diaphragm function in a model of systemic inflammation in healthy subjects. ⋯ This study shows that, in contrast to diaphragm dysfunction observed in animal models of inflammation, in vivo diaphragm contractility is augmented in the early phase after low-dose endotoxin administration in humans.
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Observational Study
Temporal Links Between Endotoxin Activity Levels and IL-6 Concentrations in Abdominal Sepsis.
In severe human peritonitis, the precise pathophysiological importance of endotoxin is controversial. Prognostic and therapeutic studies have yielded conflicting results. The current study wanted to investigate qualitative, quantitative, and temporal associations between blood endotoxin activity (EA) levels and acute inflammatory reactions. ⋯ Increasing EA levels were followed by a 90% increase of subsequent IL-6 concentrations during the next 24 to 48 h, whereas decreasing/stable EA levels were associated with slightly decreasing IL-6 concentrations (P < 0.05). Our findings suggest an altered response of the innate immune system because postinterventional EA levels did not vary with concomitant or subsequent inflammatory reactions and because inflammatory responses to newly increasing EA levels were delayed and comparatively small. Still, our results support the concept that endotoxin is a trigger of inflammatory reactions in human peritonitis.
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For the treatment of severe inflammation, sepsis and septic shock by membrane-adsorption based extracorporeal blood purification technologies, cytokines are basic targets that have to be removed effectively in order to improve the patient's health status. Although there are different adsorbents commercially available, the success of their clinical use is limited. In order to suppress systemic effects in these disease patterns, effective removal of cytokines below a critical threshold is necessary. ⋯ These results confirm the assumption, that cytokine removal from the blood should approach physiological levels in order to prevent endothelial cell activation.
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Altered mitochondrial function by excessive production of reactive oxygen species (ROS) has been considered an important factor in pathogenesis of organ failure in sepsis. ⋯ This CLP study shows that even refined, target-tailored antioxidant treatment is detrimental rather than beneficial. It is suggestive that in young female mice suffering from acute hyperinflammatory CLP sepsis, the negative role of mitochondrial ROS as the contributory factor to MODS is overestimated.