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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Endogenous purines, including inosine, have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for these effects has been shown to be between 200 and 600 mg kg(-1) because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic resistant purine analog, INO-2002, exerts anti-inflammatory effects in an animal model of acute respiratory distress syndrome. ⋯ Delaying the start of treatment by 5 h after LPS administration affected the potency of INO-2002 protective effects, with 100 but not 30 mg kg(-1) having anti-inflammatory effects. The inosine analog INO-2002 largely suppressed LPS-induced inflammation in vivo at doses lower than those needed for the naturally occurring purine inosine. These data support the proposal that purine analogs, resistant to metabolic breakdown, may represent a useful addition to the therapy of acute respiratory distress syndrome.
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Smoke inhalation injury is often complicated with pneumonia, which frequently leads to subsequent development of sepsis. Excessive NO has been shown to mediate many sepsis-related pathological responses. In the present study, we used our well-established ovine smoke inhalation and pneumonia/sepsis model to examine the hypothesis that neuronal NO synthase (NOS) may be primarily responsible for these pathological alterations. ⋯ ZK234238 significantly inhibited increased fluid accumulation as well as increased plasma nitrate/nitrite 24 h after injury. Neuronal NOS inhibition significantly reduced lung water content and attenuated inflammatory indices such as lung tissue myeloperoxidase activity, IL-6 mRNA, and reactive nitrogen species. The above results suggest that the nNOS-derived NO may be involved in the pathophysiology of sepsis-related multiorgan dysfunction.
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This article reviews current animal models and laboratory studies investigating the pathophysiology of lung contusion (LC), a common and severe condition in patients with blunt thoracic trauma. Emphasis is on studies elucidating cells, mediators, receptors, and processes important in the innate pulmonary inflammatory response that contribute to LC injury. ⋯ Studies examining combination injuries where LC is exacerbated by secondary insults such as gastric aspiration in trauma patients are also noted. The need for continuing mechanism-based research to further clarify the pathophysiology of LC injury, and to define and test potential therapeutic interventions targeting specific aspects of inflammation or surfactant dysfunction to improve clinical outcomes in patients with LC, is also emphasized.
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To test the hypothesis that dexamethasone (Dex) treatment would restore rat hepatic bile acid coenzyme A-amino acid N-acyltransferase (rBAT) expression in septic rats after cecal ligation and puncture by increasing expression of retinoic acid X receptor alpha (RXRalpha), we assessed survival rate and bile and bile salt concentration in the Dex-treated septic group and compared these results with those for a nontreated septic group, a Dex-treated nonseptic group, and a sham group. Dexamethasone treatment (0.01 mg/kg) significantly improved the survival rate and increased the bile and bile salt concentration in the bile ducts of septic rats (P = <0.05). In our assessment of bile salt-related genes, during sepsis, there were decreases in protein and mRNA expression of rBAT and cholesterol 7 alpha-hydroxylase (CYP7A1). Treatment with Dex restored expression of rBAT and RXR[alpha] but not CYP7A1, bile salt export pump, or multidrug resistance associated protein 2 (MRP2). Na+-taurocholate cotransport protein and organic anion transporting polypeptide 1 were unchanged. In addition, treatment with Dex also restored the DNA-binding activity of RXR/farnesoid-X receptor to rBAT promoter containing inverted repeat 1 sequence. In an experiment to confirm our findings, RXR[alpha] siRNA was found to significantly block Dex-induced increases in expression of rBAT in hepatocytes taken from septic rats (P < 0.01). ⋯ Dex restored the expression of rBAT in septic rats by enhancing RXR[alpha], a process that might explain the mechanism underlying Dex's anticholestatic effect.
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Mild-to-moderate therapeutic hypothermia after resuscitation from cardiac arrest is neuroprotective, but its effect on postresuscitation myocardial dysfunction is not clear. We hypothesized that therapeutic hypothermia is cardioprotective in postresuscitation. Male adult Wistar rats underwent asphyxia-induced cardiac arrest and manual resuscitation with epinephrine. ⋯ In conclusion, postresuscitation mild-to-moderate therapeutic hypothermic is cardioprotective in the asphyxia-induced cardiac arrest animal model. It stabilizes hemodynamics, improves short-term survival, and decreases myocardial damage. The cardioprotective effect is associated with Akt and ERK1/2 activation in signal transduction.