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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Lung contusion is a common problem from blunt chest trauma caused by mechanical forces and by exposure to blast overpressure, often with fatal consequences. Lung contusion is also a risk factor for the development of pneumonia, severe clinical acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Infiltrating neutrophils are considered to be central mediators of lung injuries after blunt trauma. ⋯ N-Acetylcysteine amide significantly reduced infiltration of neutrophils and CD11b mRNA activation in lungs, and completely blocked activation of MIP-1, MCP-1 and CINC-1 mRNA. The relatively higher inhibition of chemokine mRNAs compared with reduction in MPO activity and CD11b is in accordance with an antioxidant effect of NACA on reactive oxygen species (ROS) accumulation, rather than by an effect on neutrophil sequestration. The inhibition of HO-1 mRNA activation after blast was likely also related to the drug antioxidant effect.
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The reduced pressure response to norepinephrine during sepsis has directed our interest to the regulation of alpha1-adrenergic receptors. Because nuclear factor (NF)-kappaB occupies a prominent role in the inflammatory cascade, we hypothesized that NF-kappaB downregulates alpha1-receptors by liberation of proinflammatory cytokines and thereby contributes to septic circulatory failure. Sepsis was induced by cecal ligation and puncture (CLP) in wild-type mice and mice with deficiencies for proinflammatory cytokines, and mice were injected with TNF-alpha, IL-1beta, IFN-gamma, or IL-6. ⋯ Furthermore, inhibiting NF-kappaB activity by siRNA reduced the production of cytokines, prevented circulatory failure and downregulation of alpha1-receptors, and improved survival of septic mice. Our findings indicate that NF-kappaB has a central role in augmenting proinflammatory cytokine production during sepsis, which in turn downregulates alpha1-receptor expression. Our data further define a critical role for NF-kappaB in the pathogenesis of septic shock, indicating that targeting NF-kappaB is a desired therapeutic strategy to treat septic vasoplegia.
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The objective of this study was to evaluate the rivastigmine effect on habituation to the open-field memory impairment observed in sepsis survivor rats. A prospective, controlled experiment was designed. The setting was an animal basic science laboratory, and the subjects were male Wistar rats weighing 300 to 350 g. ⋯ In the test session, there was a significant reduction in both crossings and rearings in the sham and sepsis group that received rivastigmine when compared with the training, indicating memory acquisition. In contrast, in the sepsis group that did not receive rivastigmine there was no difference in crossings and rearings between training and test session, indicating an impairment in memory acquisition. Therefore, rivastigmine reversed cognitive impairment in sepsis survivor rats in the open-field test.
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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.