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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Induction of the antiviral cytokine interferon alpha/beta (IFN-alpha/beta) is common in many viral infections. The impact of ongoing antiviral responses on subsequent bacterial infection is not well understood. In human disease, bacterial superinfection complicating a viral infection can result in significant morbidity and mortality. ⋯ Inhibition of NF-kappaB by parthenolide did reduce IFN-alpha-mediated potentiation of the cytokine response and lethality from septic shock. Our data demonstrate that pathways activated early during many viral infections can have a detrimental impact on the outcome of subsequent bacterial infection. These pathways may be critical to understanding the heightened morbidity and mortality from bacterial superinfection after viral infection in human disease.
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Sepsis remains a serious clinical problem despite intense efforts to improve survival. In this study, the efficacy of ertapenem combined with the cathelicidin tritrpticin was investigated in two rat models of septic shock. Main outcome measures were bacterial growth in blood, peritoneum, spleen, liver, and mesenteric lymph nodes; endotoxin, interleukin 6, and tumor necrosis factor alpha concentrations in plasma; and lethality. ⋯ Treatment with tritrpticin resulted in significant decrease in plasma endotoxin and cytokine levels, whereas ertapenem exerted opposite effect. The combination between tritrpticin and ertapenem proved to be the most effective treatment in reducing all variables measured. In conclusion, tritrpticin enhances ertapenem efficacy in gram-negative septic shock rat models.
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Peroxisome proliferator-activated receptor-gamma (PPARgamma) and liver X receptor-alpha (LXRalpha) are nuclear ligand-activated transcription factors, which regulate lipid metabolism and inflammation. Murine J774.2 macrophages were stimulated with Escherichia coli lipopolysaccharide (concentration, 10 microg/mL) with or without the PPARgamma ligand, 15-deoxy-Delta prostaglandin J2 (15d-PGJ2), or the LXRalpha ligands, 22(R)-hydroxycholesterol and T0901317 (concentration range, 0.01-10 micromol/L), alone or in combination. Nitric oxide (NO) metabolites and tumor necrosis factor alpha production, inducible NO synthase expression, and mitochondrial respiration were measured. ⋯ Immunoprecipitation experiments revealed that PPARgamma interacted with LXRalpha. Our data demonstrate that the PPARgamma ligand, 15d-PGJ2, and the LXRalpha ligands, 22(R)-hydroxycholesterol and T0901317, although binding to different nuclear receptors (i.e., PPARgamma and LXRalpha, respectively), affect mediator production through common cell signaling events and exert a synergistic potentiation in a combined treatment at suboptimal concentrations. Thus, our data suggest that PPARgamma and LXRalpha may interact in controlling the inflammatory response in macrophages.
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We investigated whether (endogenous) hydrogen sulfide (H2S) protects the heart against myocardial ischemia and reperfusion injury. Furthermore, we investigated whether endogenous H2S is involved in the protection afforded by (1) ischemic preconditioning and (2) the second window of protection caused by endotoxin. The involvement of one of the potential (end) effectors of the cardioprotection afforded by H2S was investigated using the mitochondrial KATP channel blocker, 5-hydroxydecanoate (5-HD; 5 mg/kg). ⋯ The delayed cardioprotection afforded by endotoxin was abolished by 5-HD or PAG. In contrast, PAG (50 mg/kg) did not affect the cardioprotective effects of ischemic preconditioning. These findings suggest that (1) endogenous H2S is produced by myocardial ischemia in sufficient amounts to limit myocardial injury and (2) the synthesis or formation of H2S by cystathionine-gamma-lyase may contribute to the second window of protection caused by endotoxin.
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Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a major role in the pathogenesis of sepsis. Some studies have indicated that glucocorticoids increase MIF production in physiological conditions. The goal of this study was to determine whether glucocorticoid treatment also upregulates MIF production in sepsis. ⋯ Sepsis induced by cecal ligation and puncture produced a marked increase in MIF and cytokine levels in plasma and peritoneal fluid. Treatment with dexamethasone 10 mg/kg decreased MIF levels in plasma after 18 h, but there was no effect of dexamethasone on MIF production locally in the peritoneal cavity or in the liver, lungs, heart, or kidneys. We conclude that glucocorticoid treatment does not upregulate MIF production in sepsis.