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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Treatment with bone morphogenetic protein 2 limits infarct size after myocardial infarction in mice.
Various strategies have been devised to reduce the clinical consequences of myocardial infarction, including acute medical care, revascularization, stem cell transplantations, and more recently, prevention of cardiomyocyte cell death. Activation of embryonic signaling pathways is a particularly interesting option to complement these strategies and to improve the functional performance and survival rate of cardiomyocytes. Here, we have concentrated on bone morphogenetic protein 2 (BMP-2), which induces ectopic formation of beating cardiomyocytes during development in the mesoderm and protects neonatal cardiomyocytes from ischemia-reperfusion injury. ⋯ In vitro, BMP-2 increases the frequency of spontaneously beating neonatal cardiomyocytes and the contractile performance under electrical pacing at 2 Hz, preserves cellular adenosine triphosphate stores, and decreases the rate of apoptosis despite the increased workload. In addition, BMP-2 specifically induced phosphorylation of Smad1/5/8 proteins and protected adult cardiomyocytes from long-lasting hypoxia-induced cellular damage and oxidative stress without activation of the cardiodepressant transforming growth factor-β pathway. Our data suggest that BMP-2 treatment may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by improving the contractility of cardiomyocytes and preventing cardiomyocyte cell death.
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Biofilms production is a central feature of nosocomial infection of catheters and other medical devices used in resuscitation and critical care. However, the very effective biofilm forming pathogen Staphylococcus epidermidis often produces a modest host inflammatory response and few of the signs and symptoms associated with more virulent pathogens. To examine the impact of bacterial biofilm formation on provocation of an innate immune response, we studied the elaboration of the major complement anaphylatoxin C5a by human serum upon contact with S. epidermidis biofilms. ⋯ Experimental results were used to inform a physiologically based pharmacokinetic model of C5a release by an infected central venous catheter, one of S. epidermidis' primary means of causing human disease. These simulations revealed that the magnitude of C5a release on a superior vena cava catheter completely covered with S. epidermidis would be lower than necessary to alert circulating leukocytes. Combined, the experimental and computational results are highly consistent with clinical observations in which the clinical signs of central line-associated bloodstream infection are often muted in association with this important pathogen.
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Firm neutrophil (PMN)-endothelial (EC) adhesion is crucial to the PMN-mediated hyperinflammation observed in acute lung injury. Hypertonic saline (HTS) used for resuscitation of hemorrhagic shock has been associated with a decreased incidence of PMN-mediated lung injury/acute respiratory distress syndrome. We hypothesize that physiologically accessible hypertonic incubation (170 vs. 140 mM, osmolarity ranging from 360 to 300 mOsm/L) inhibits proinflammatory activation of human pulmonary microvascular endothelial cells (HMVECs). ⋯ Despite this basal activation, hyperosmolar incubation attenuated TNF-α-stimulated IL-8 release and ICAM-1 surface expression and subsequent PMN adherence, while p38 MAPK inhibition did not further influence the effects of hyperosmolar conditions on ICAM-1 surface expression. In addition, TNF-α induced nuclear factor-κB DNA binding, but HTS conditions attenuated this by 31% (P < 0.01). In conclusion, HTS reduces PMN-HMVEC adhesion and TNF-α-induced proinflammatory activation of primary HMVECs via attenuation of nuclear factor-κB signaling.
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Myocardial depression in septic shock is well known, but its pathophysiological genesis is incompletely understood. To assess the incidence and extent of stress-induced histologic myocardial alterations in septic shock, a prospective, observational, combined clinical and postmortem study was conducted, and 20 patients dying from septic shock were included. Exclusion criteria were younger than 18 years, pregnancy, open heart surgery or cardiopulmonary resuscitation, acute neurologic diseases, pheochromocytoma, and forensic autopsy. ⋯ Maximum norepinephrine doses correlated with the extent of mononuclear infiltrates in the left ventricular anterior wall (Spearman-Rho, r = 0.519; P = 0.02). The total duration of catecholamine therapy was correlated with the extent of mononuclear infiltrates in the apex (Spearman-Rho, r = 0.571; P = 0.009) and right atrium (Spearman-Rho, r = 0.535; P = 0.02). In conclusion, our results suggest that histologic lesions potentially indicative of stress-induced cardiotoxicity can be observed in most patients dying from septic shock.
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Interleukin 6 (IL-6) is an inflammatory cytokine known to be elevated in chronic diseases and after insults such as trauma and infection. Although necessary for the development of B cells and Th17 cells, IL-6, at elevated levels, can also cause tissue damage and lead to a rise in inflammation. Previous work in our laboratory has shown that IL-6 is increased both systemically and in multiple organ systems including the ileum after ethanol exposure and burn injury. ⋯ Interleukin 6-knockout mice given ethanol and burn injury also had reduced intestinal damage; however, no changes in bacterial translocation or tight junction protein localization were observed as compared with similarly treated wild-type mice. These data suggest that IL-6 may have a role in intestinal tissue damage observed after the combined insult of binge ethanol exposure and burn injury, although complete loss of IL-6 does not seem to be beneficial in this model. Modulation of IL-6 may present a new option for preventing intestinal damage and associated inflammation after a combined insult of ethanol exposure and burn injury.