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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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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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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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.
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Review Historical Article
The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies.
Increasing evidence has demonstrated that aggressive crystalloid-based resuscitation strategies are associated with cardiac and pulmonary complications, gastrointestinal dysmotility, coagulation disturbances, and immunological and inflammatory mediator dysfunction. As large volumes of fluids are administered, imbalances in intracellular and extracellular osmolarity occur. Disturbances in cell volume disrupt numerous regulatory mechanisms responsible for keeping the inflammatory cascade under control. ⋯ Numerous investigators have evaluated potential risk factors for developing abdominal compartment syndrome and have universally noted the excessive use of crystalloids as the primary determinant. Resuscitation regimens that cause early increases in blood flow and pressure may result in greater hemorrhage and mortality than those regimens that yield comparable flow and pressure increases late in resuscitation. Future resuscitation research is likely to focus on improvements in fluid composition and adjuncts to administration of large volume of fluid.
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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.