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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Using a modified uncontrolled hemorrhage shock model with massive splenic and vascular injury, we evaluated outcome and tissue oxidation injury with different resuscitation interventions during prehospital and hospital phases. The aim of our study was to explore the effect of initial fluid resuscitation on subsequent treatment of uncontrolled hemorrhagic shock in rats. Uncontrolled hemorrhagic shock was produced in 114 Wistar rat by sharp transection both of the splenic parenchyma at one location between the major branches of the splenic artery into the spleen and of one of the major branches of the splenic artery. ⋯ The animals whose MAP was kept higher than 80 mmHg had significantly higher MDA content and lower T-AOC than those whose MAP was maintained 40, 50, or 60 mmHg during the prehospital phase. In the hospital phase, resuscitation with balanced saline and whole blood not only relieved tissue damage but also improved the survival, as indicated by 44.4% survival rate in the rats that resuscitated to a MAP of 80 or 100 mmHg in the prehospital phase. These results suggested that in our uncontrolled hemorrhagic shock model, limited resuscitation in the prehospital phase had benefit for subsequent treatment in the hospital phase in terms of alleviated tissue damage and improved survivorship.
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Cardiac myocytes are capable of synthesizing tumor necrosis factor alpha (TNF-alpha), interleukin-1, and interleukin-6 (IL-1 and IL-6). p38 mitogen-activated protein kinase (MAPK) has been implicated in oxidant-stress-induced myocardial TNF-alpha production; however, the extent to which this kinase contributes to endotoxin-induced contractile dysfunction, as well as TNF-alpha, IL-1alpha, IL-1beta, and IL-6 production, in a bloodless model of endotoxin-induced myocardial dysfunction is unknown. Isolated rat hearts were perfused (Langendorff), and myocardial contractile function continuously recorded, during direct antegrade endotoxin infusion, with and without prior p38 MAPK inhibition. Ventricular p38 MAPK activation (phospho-p38 MAPK Western), cytokine mRNA (RT-PCR), and protein (ELISA) were determined. ⋯ To determine the relative effect of TNF-alpha in inducing IL-1alpha, IL-1beta, and IL-6 production, TNF-alpha was sequestered during endotoxin infusion, and TNF-alpha, IL-1beta, and IL-6 protein levels were measured. Interestingly, TNF-alpha sequestration alone significantly decreased myocardial IL-1beta and IL-6 production. We conclude that p38 MAPK is involved in endotoxin-induced myocardial contractile dysfunction and myocardial TNF-alpha production; however, p38 MAPK's involvement in IL-1 and IL-6 production may be indirectly mediated by TNF-alpha.
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Inhibition of poly (ADP-ribose) polymerase attenuates acute lung injury in an ovine model of sepsis.
It is known that in various pathophysiological conditions, reactive oxidants cause DNA strand breakage and subsequent activation of the nuclear enzyme poly(ADP ribose) polymerase (PARP). Activation of PARP results in cellular dysfunction. We hypothesized that pharmacological inhibition of PARP reduces the damage in the ovine model of acute lung injury (ALI). ⋯ INO-1001 treatment reduced pulmonary histological injury and attenuated poly (ADP-ribose) accumulation in the lung. In conclusion, inhibition of PARP improved the ALI after smoke inhalation and pneumonia. The results suggest that the activation of PARP plays a role in the pathophysiology of ALI in sheep.
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Hepatic microcirculatory disorders such as narrowing of sinusoids after hemorrhagic shock play a major role in the pathogenesis of organ failure. It is known that the balance of vasoactive mediators such as endothelin and nitric oxide (NO) regulate microvascular perfusion, including the diameter of hepatic sinusoids. The present study was designed to evaluate the role of exogenous substitution of NO by S-nitroso-albumin (S-NO-HSA) in the prevention of pathophysiological alterations of hepatic microcirculation. ⋯ Sinusoidal perfusion was significantly higher in the S-NO-HSA group than in the HSA group (HSA: 50,934 +/- 1,382 microm3/s; S-NO-HSA: 78,120 +/- 2,348 microm3/s, P < 0.05). Reversible leukocyte adhesion to sinusoidal endothelium, an indicator of the inflammatory response, was significantly reduced in the S-NO-HAS-treated group. The findings of this study in a rat model of hemorrhagic shock suggest that NO substitution by S-NO-HSA during resuscitation attenuates both early and late hepatic microcirculatory disturbances as well as the increase in leukocyte adherence.
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Sepsis is the most common cause of death in intensive care units worldwide. The basic pathophysiologic defect in sepsis, causing functional abnormalities in many organ systems, remains elusive. One potential cause is disruption of oxidative phosphorylation in mitochondria. ⋯ Both loss of heme and loss of subunit I could explain the observed irreversible inhibition of cytochrome c oxidase. Noncompetitive inhibition of cytochrome c oxidase may interrupt oxidative phosphorylation, leading to sepsis-associated cardiac depression. Importantly, this abnormality may underlie sepsis-associated dysfunction in other organ systems.