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 the past decades, increased concentrations of the signaling molecule adenosine have been shown to play an important role in the prevention of tissue damage evoked by several stressful circumstances. During systemic inflammation, the circulating adenosine concentration increases rapidly, even up to 10-fold in septic shock patients. ⋯ Importantly, correct interpretation of the effects of adenosine is highly related to the model of inflammation used, e.g., administration of endotoxin or live bacteria. This review will discuss the potential role for adenosine as an immunomodulating and cytoprotective signaling molecule and will discuss its potential role in the treatment of the patient suffering from sepsis.
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In low-flow states, such as circulatory shock, both fluids and catecholamines are often coadministered. We have previously found that adrenergic agents alter volume expansion after a fluid bolus. The present study tested the volume expansion properties of dobutamine and norepinephrine in sheep treated with (series 1) and without (series 2) a fluid bolus. ⋯ Dobutamine and norepinephrine increased ΔPV over time, 5.1 ± 0.5 and 4.0 ± 0.5 mL x kg(-1), respectively. At study end, UOP was lowest in dobutamine. Norepinephrine resulted in loss of ΔEVV fluid. data suggest a novel role for adrenergic receptors in regulating vascular and EVV expansion. β-Adrenergic agonists enhance vascular volume expansion, whereas α-adrenergic agonists eliminate extravascular fluid.
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Localized tissue hypoxia is a feature of infection and inflammation, resulting in the upregulation of the transcription factors hypoxia-inducible factor 1α and nuclear factor κB (NF-κB) via inhibition of oxygen sensing hydroxylase enzymes. Previous studies have demonstrated a beneficial role for the hydroxylase inhibitor dimethyloxallyl glycine (DMOG) in inflammatory conditions, including experimental colitis, by regulating the activity of hypoxia-inducible factor 1 and NF-κB. We have demonstrated in vivo that pretreatment with DMOG attenuates systemic LPS-induced activation of the NF-κB pathway. ⋯ Dimethyloxallyl glycine treatment of mice promotes M2 polarization in macrophages within the peritoneal cavity, resulting in the downregulation of proinflammatory cytokines such as TNF-α. In addition, in vivo DMOG treatment upregulates IL-10 expression, specifically in the peritoneal B1 cell population. This study demonstrates cell type-specific roles for hydroxylase inhibition in vivo and provides insight into the mechanism underlying the protection conveyed by DMOG in models of endotoxic shock.
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High mobility group box 1 (HMGB1), a delayed mediator of proinflammatory cytokines, could initiate and amplify inflammatory responses to infection, injury, and other inflammatory stimuli, and it has emerged as a potential therapeutic target for inflammatory diseases. The overexpression of HMGB1 in endothelial cells has been proved to contribute to the development of these diseases. Because many proinflammatory cytokines expression were suppressed by thiazolidinediones (TZDs), agonists for nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), whether TZDs can inhibit HMGB1 expression and function is of great interest, however, it remains unknown. ⋯ A luciferase reporter assay showed that troglitazone inhibited not only the transcriptional activation of the HMGB1 promoter but also activities of heterologous promoters driven by nuclear factor κB (NF-κB) or activator protein 1 (AP-1) response elements. Altogether, these data suggest that NF-κB and AP-1 may participate in the inhibitory effect on HMGB1 transcription induced by troglitazone. Activation of PPARγ by troglitazone is effective for HMGB1 inhibition via suppressing NF-κB and AP-1 transcriptional activity in endothelial cells, which provides a new potential strategy to suppress excessive HMGB1 in inflammatory diseases.
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Endothelial progenitor cells (EPCs) and polymorphonucleated leukocytes (PMNLs) migrate to and accumulate at the site of tissue injury where they express complementary sets of surface receptors (CD11b/CD18, CD54), suggesting a possible cellular interaction. Trauma-activated PMNLs release inflammatory mediators and reactive oxygen species (ROS) produced by the NADPH oxidase, which may negatively impact EPCs. To characterize the interactions between PMNLs and EPCs, we identified common surface receptors and measured the role played by NADPH oxidase and neutrophil elastase. ⋯ Our results demonstrate that EPCs and PMNLs do interact via complementary receptors and that this interaction results in PMNL-derived ROS-induced EPC damage. The effect of neutrophil-derived elastase was found to be negligible. These findings suggest that EPC damage by activated PMNLs may contribute to impaired wound healing observed after severe trauma.