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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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.
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Genetically identical mice have a heterogeneous response to antibiotic therapy in sepsis, with only a subset deriving therapeutic benefit. We sought to determine whether the severity of a septic insult correlates with the survival benefit conferred by antibiotics. We also sought to determine whether antibiotics given 12 h after injury alter survival in animals predicted to die based upon high interleukin (IL)-6 levels drawn 6 h earlier. ⋯ Although antibiotics decreased mortality overall, all animals with IL-6 levels greater than 14,000 pg/mL (n = 13) died, regardless of whether they received antibiotics or the gauge of needle used. These results indicate that antibiotics improve outcome in murine sepsis, regardless of injury severity. Furthermore, there is a threshold IL-6 level that can be identified 6 h after sepsis above which animals are destined to die, and antibiotic treatment does not alter their outcome.