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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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.
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Hepatocellular apoptosis commonly occurs in ischemia/reperfusion (I/R) injury. The binding of tumor necrosis factor (TNF) to TNF receptor 1 (TNFR1) leads to the formation of a death-inducing signaling complex (DISC), which subsequently initiates a caspase cascade resulting in apoptosis. Heme oxygenase 1 (HO-1) confers cytoprotection against cell death in I/R injury and inhibits stress-induced apoptotic pathways in vitro. ⋯ In the mitochondrial fraction, TNFR1-associated caspase-8 was increased after I/R. These increases were attenuated by hemin; zinc protoporphyrin eliminated this effect. Our findings suggest that the cytoprotective effects of HO-1 are mediated by suppression of TNF/TNFR1-mediated apoptotic signaling, specifically by modulating apoptotic DISC formation and mitochondrial TNFR1 translocation during hepatic I/R.
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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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A reduction of the neutrophil migration into the site of infection during cecal ligation and puncture-induced sepsis increases host mortality. Inhibition of heme oxygenase (HO) prevents this neutrophil paralysis and improves host survival in the cecal ligation and puncture model. Taking into account that almost 50% of all sepsis cases are a consequence of pneumonia, we designed the present study to determine the role of HO in an experimental model of pneumonia-induced sepsis. ⋯ The pretreatment of mice subjected to pneumonia-induced sepsis with ZnDPBG (zinc deuteroporphyrin 2,4-bis glycol), a nonspecific HO inhibitor, increased the number of neutrophils in the bronchoalveolar spaces, reduced the bacterial load at the site of infection, and prevented the upregulation of CD11b and the downregulation of CXCR2 on blood neutrophils. Moreover, the pretreatment with ZnDPBG decreased alveolar collapse, attenuating the deleterious changes in pulmonary mechanics and gas exchanges and, as a consequence, improved the survival rate of mice from 0% to ∼20%. These results show that heme oxygenase is involved in the pathophysiology of pneumonia-induced sepsis and suggest that HO inhibitors could be helpful for the management of this disease.