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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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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Burn injury initiates an enhanced inflammatory condition referred to as the systemic inflammatory response syndrome or the two-hit response phenotype. Prior reports indicated that macrophages respond to injury and demonstrate a heightened reactivity to Toll-like receptor stimulation. Since we and others observed a significant increase in splenic GR-1 F4/80 CD11b macrophages in burn-injured mice, we wished to test if these macrophages might be the primary macrophage subset that shows heightened LPS reactivity. ⋯ However, further investigations showed that LPS-induced TNF-α production was significantly influenced by CD4 T cells. Taken together, these data indicate that GR-1 F4/80 CD11b macrophages represent the primary macrophage subset that expands in response to burn injury and that CD4 T cells do not influence the GR-1 macrophage expansion process, but do suppress LPS-induced TNF-α production. These data suggest that modulating GR-1 macrophage activation as well as CD4 T cell responses after severe injury may help control the development of systemic inflammatory response syndrome and the two-hit response phenotype.
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The mechanisms contributing to sepsis vascular dysfunction are not well known. We tested the hypothesis that peroxynitrite scavenging ameliorates sepsis-induced macrovascular and microvascular dysfunction. Male Sprague-Dawley rats were killed 48 h after cecal ligation (n = 15) and puncture or sham procedure (n = 15). ⋯ Sepsis induced (i) in macrovessels, impairment of norepinephrine-induced contractions; (ii) in microvessels, impairment in norepinephrine-induced contractions and acetylcholine-induced relaxations; (iii) aortic and microvascular tissue increased reactivity to 3-nitrotyrosine, oxidized dihydroethidium, NOS2, and increased expression of NOS2, as well as increased expression of NOX-1 in microvascular tissue. Contractile responses in aortic and microvascular rings improved by ex vivo treatment with MnTMPyP and tempol, whereas vascular relaxation in microvessels improved only with MnTMPyP. Peroxynitrite scavenging protects from vascular dysfunction in sepsis.
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Acute kidney injury (AKI) leads to increased lung microvascular permeability, leukocyte infiltration, and upregulation of soluble inflammatory proteins in rodents. Most work investigating connections between AKI and pulmonary dysfunction, however, has focused on characterizing whole lung tissue changes associated with AKI. Studies at the cellular level are essential to understanding the molecular basis of lung changes during AKI. ⋯ Further experiments using an in vitro rat pulmonary microvascular EC system revealed that AKI serum induced functional cellular changes related to apoptosis, including structural actin alterations and phosphatidylserine translocation. Analysis and segregation of both upregulated and downregulated genes into functional roles suggest that these transcriptional events likely participate in the transition to an activated proinflammatory and proapoptotic EC phenotype during AKI. Further mechanistic analysis of EC-specific events in the lung during AKI might reveal potential novel therapeutic targets for the deleterious kidney-lung crosstalk in the critically ill patient.