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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Clinical Trial
Interplay between the acute inflammatory response and heart rate variability in healthy human volunteers.
The autonomic nervous system and the inflammatory response are intimately linked. Heart rate variability (HRV) analysis is a widely used method to assess cardiac autonomic nervous system activity, and changes in HRV indices may correlate with inflammatory markers. Here, we investigated whether baseline HRV predicts the acute inflammatory response to endotoxin. ⋯ Heart rate variability indices do not predict the acute inflammatory response in a standardized model of systemic inflammation. Although the acute inflammatory response results in HRV changes, no correlations with inflammatory cytokines were observed. Therefore, the magnitude of endotoxemia-related HRV changes does not reflect the extent of the inflammatory response.
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We investigated the therapeutic effects of parenteral fish oil (FO) on survival and fatty acid profile in plasma and erythrocyte membranes, T-lymphocyte subsets, and plasma cytokines in a rat model of sepsis. Adult male Sprague-Dawley rats were subjected to cecal ligation and puncture-induced sepsis. For recovery, central venous catheterization was performed 2 days before sepsis was induced. ⋯ Fish oil-supplemented TPN attenuated the production of high-mobility group box 1 and IL-10 in plasma. Moreover, parenteral FO decreased the bacterial loads in peritoneal lavage, blood, lung, and spleen. The present study suggests that FO-supplemented TPN initiated at the onset of sepsis improves survival, beneficially alters the lipids profile in plasma and erythrocyte membrane, modulates immune function, and regulates inflammatory response in a rat model.
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This study tests the hypothesis that pretreatment and/or posttreatment with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an inducer of adenosine monophosphate-activated protein, will extend the golden hour of survival time in rats subjected to severe hemorrhagic shock in the absence of available fluid resuscitation. Three days before hemorrhage, at 24-h intervals, animals were given three i.p. injections of AICAR (pretreatment) or saline (control/posttreatment). At the end of hemorrhage, animals (control/pretreatment) received a single i.v. injection of saline, whereas the posttreatment group received a single i.v. injection of AICAR (posttreatment). ⋯ Heart rate for both the pretreatment and posttreatment animals was also significantly (P < 0.01) lower after 30 min versus saline control group, pretreatment: 247 ± 13 beats/min; posttreatment: 240 ± 20 beats/min; saline: 415 ± 18 beats/min. Lactate levels were also significantly reduced 6.3 ± 0.71 mmol/L (pretreatment), 7.1 ± 0.47 mmol/L (posttreatment), 8.9 ± 0.21 mmol/L (saline). The improvement in hemodynamic stability is reflected in the significant increase in the golden-hour survival time in animals subjected to severe hemorrhagic shock.
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Although aberrant fibrinolysis and plasminogen activator inhibitor 1 (PAI-1) are implicated in acute lung injury, the role of this serpin in the pathogenesis of wood bark smoke (WBS)-induced acute lung injury (SIALI) and its regulation in resident lung cells after exposure to smoke are unclear. A total of 22 mechanically ventilated pigs were included in this study. Immunohistochemical analyses were used to assess fibrin and PAI-1 in the lungs of pigs with SIALI in situ. ⋯ In pleural mesothelial cells, lung fibroblasts, and alveolar type II cells, PAI-1 mRNA was stabilized by WBS extract and contributed to induction of PAI-1. The mechanism involves dissociation of a novel 6-phospho-d-gluconate-NADP oxidoreductase-like PAI-1 mRNA binding protein from PAI-1 mRNA. Exposure to WBS induces prominent airway and mesothelial expression of PAI-1, associated with florid distribution of fibrin in SIALI in vivo Wood bark smoke components induce PAI-1 in vitro in part by stabilization of PAI-1 mRNA, a newly recognized pathway that may promote extravascular fibrin deposition and lung dysfunction in SIALI.
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Indirect acute lung injury (ALI) is a common manifestation in critically ill patients. Using a model of indirect ALI in mice, our laboratory has shown that local/pulmonary inhibition of extrinsic death receptor protein (Fas) leads to a decrease in lung inflammation and improved survival. However, it is unknown if local, i.e., autocrine/paracrine, inhibition of Fas ligand (FasL) affects Fas-expressing target cells itself or blockade of the actions of a more distal/endocrine source of FasL that accounts for these findings. ⋯ After intratracheal delivery of FasL siRNA, there was a significant decrease in inflammatory cytokines, myeloperoxidase activity, and caspase 3 activity in lung tissue along with protein leak as compared with controls. There was no difference found in these various outcome markers between those treated with intravenously administered FasL siRNA versus controls. The observation that local silencing of FasL, as opposed to distal/systemic silencing, ameliorates the effects of indirect ALI suggests not only that FasL produced in an autocrine/paracrine fashion in local tissues has pathological consequences within the lungs, but also that FasL might be a valuable pulmonary therapeutic target.