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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IL-1beta, TNF-alpha, cytokine-induced neutrophil chemoattractant-2alpha/beta, and IL-10 measurements were performed in elicited peritoneal cells from control, diabetic, and insulin-treated diabetic rats. Production/liberation of these cytokines was decreased in elicited peritoneal cells from diabetic rats. These changes were abolished by insulin treatment of diabetic rats. The alterations observed might be involved in the impaired inflammatory response and high occurrence of apoptosis observed in neutrophils under diabetic states.
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Endotoxic shock is a systemic inflammatory response that is associated with an increase in nitric oxide production and a decrease in the formation of 20-hydroxyeicosatetraenoic acid (20-HETE), which may contribute to the fall in blood pressure and vascular reactivity. The present study examined the effects of a synthetic analogue of 20-HETE, N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-HEDGE), on the fall in blood pressure and vascular responsiveness to vasoscontrictors and acetylcholine in rats treated with endotoxin. The MAP fell by 31 mmHg, and the heart rate rose by 90 beats/min in male Wistar rats treated with endotoxin (10 mg/kg, intraperitoneally). ⋯ The effects of endotoxin were prevented by 5,14-HEDGE (30 mg/kg, s.c.) given 1 h after injection of endotoxin. Furthermore, a competitive antagonist of vasoconstrictor effects of 20-HETE, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (30 mg/kg, s.c.), prevented the beneficial effects of 5,14-HEDGE on MAP and vascular tone in rats treated with endotoxin. These data are consistent with the view that a fall in the production of 20-HETE contributes to the fall in MAP and vascular reactivity in rats treated with endotoxin, and that 5,14-HEDGE has a beneficial effect.
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The fundamental mechanisms that underlie endotoxin tolerance remain to be elucidated, and the clinical significance of endotoxin tolerance in the context of active systemic infection remains in question. We hypothesized that the endotoxin tolerance phenotype would result in decreased inflammation at the expense of altered bacterial clearance and, thus, higher mortality in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Endotoxin tolerance was induced in C57Bl/6 mice with 5 mg/kg LPS or vehicle 18 h before subsequent CLP. ⋯ Endotoxin tolerance significantly improved bacterial clearance in both blood and peritoneal fluid after CLP. Similarly, ex vivo phagocytosis by primary peritoneal macrophages and RAW264.7 murine peritoneal macrophages was significantly improved after induction of the endotoxin tolerance phenotype. Contrary to our original hypothesis, we conclude that endotoxin tolerance significantly attenuates the host inflammatory response, augments bacterial clearance, and improves survival in this murine model of polymicrobial sepsis.
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The serine/threonine glycogen synthase kinase 3beta (GSK-3beta) is abundant in the central nervous system, particularly in the hippocampus, and plays a pivotal role in the pathophysiology of a number of diseases, including neurodegeneration. This study was designed to investigate the effects of GSK-3beta inhibition against I/R injury in the rat hippocampus. Transient cerebral ischemia (30 min) followed by 1 h of reperfusion significantly increased generation of reactive oxygen species and modulated superoxide dismutase activity; 24 h of reperfusion evoked apoptosis (determined as mitochondrial cytochrome c release and Bcl-2 and caspase-9 expression), resulted in high plasma levels of TNF-alpha and increased expression of cyclooxygenase-2, inducible nitric oxide synthase, and intercellular adhesion molecule-1. ⋯ These beneficial effects were associated with a reduction of I/R-induced activation of the mitogen-activated protein kinases JNK1/2 and p38 and nuclear factor-kappaB. The present study demonstrates that TDZD-8 protects the brain against I/R injury by inhibiting GSK-3beta activity. Collectively, our data may contribute to focus the role of GSK-3beta in cerebral I/R.
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Krüppel-like factor 4 (KLF4) is an evolutionarily conserved zinc finger-containing transcription factor with diverse regulatory functions in cell growth, proliferation, differentiation, and embryogenesis. In our previous study, we found that KLF4 mRNA was up-regulated more than 10-fold in adult mice lung tissues after endotoxin stimuli, and that KLF4 can regulate the expression of IL -10, an early inflammatory mediator. To determine whether KLF4 influences the expression and release of high-mobility group box 1 (HMGB1), an important late inflammatory mediator, which contains two potential KLF4-binding elements in its promoter, pcDNA3.1-KLF4 expression plasmid or KLF4 antisense oligonucleotide was transfected into RAW264.7 macrophages, the expression and release of HMGB1 were examined by reverse-transcriptase-polymerase chain reaction and Western blot, respectively. ⋯ Moreover, compared with the control group, the release of HMGB1 was increased after KLF4 overexpression after LPS treatment, whereas the release of HMGB1 was decreased after KLF4 deficiency in response to LPS. Electrophoretic mobility shift assay results showed the binding of KLF4 to the oligonucleotides designed according to the HMGB1 promoter, and the binding activity was increased in response to LPS stimulation. These results indicate that KLF4 plays an important role in regulating the expression of HMGB1 in normal condition, as well as the translocation and release of HMGB1 in response to LPS.