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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Relationship of basal heart rate variability to in vivo cytokine responses after endotoxin exposure.
Autonomic inputs from the sympathetic and parasympathetic nervous systems, as measured by heart rate variability (HRV), have been reported to correlate to the severity injury and responses to infectious challenge among critically ill patients. In addition, parasympathetic/vagal activity has been shown experimentally to exert anti-inflammatory effects via attenuation of splanchnic tissue TNF-alpha production. We sought to define the influence of gender on HRV responses to in vivo endotoxin challenge in healthy humans and to determine if baseline HRV parameters correlated with endotoxin-mediated circulating cytokine responses. ⋯ We found that gender, body mass index, or resting heart rate did not significantly alter the HRV response after endotoxin exposure. Using entropy analysis, we observed that females had significantly higher entropy values at 24 h after endotoxin exposure. Using a serially sampling protocol for cytokine determination, we found a significant correlation of several baseline HRV parameters (percentage of interval differences of successive interbeat intervals more than 50 ms, r = 0.42, P < 0.05; high-frequency variability, r = 0.4, P < 0.05; and low-frequency/high-frequency ratio, r = -0.43, P < 0.05) on TNF-alpha release after endotoxin exposure.
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Efforts to improve survival from sepsis are focusing increasingly on intervention during the earliest stages of this disease. The importance of derangements in microvascular flow in patients with established sepsis is well recognized. However, little data are available to describe microvascular changes in early sepsis. ⋯ Sepsis results in derangements of microvascular flow, which can be identified in the early stages of this disease. These abnormalities are more marked in the most severely ill patients. Further research is required to fully characterize the effects of sepsis on microvascular function.
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Microcirculatory dysfunction plays a pivotal role in the clinical development and manifestation of severe sepsis and as a marker for mortality. During this process, endothelial damage is characterized by structural and functional alterations that contribute to a great extent to tissue edema. Recent findings revealed the vagus nerve as an important transmitter of the cholinergic anti-inflammatory pathway. ⋯ On the other hand, venular wall shear rate showed no differences. In summary, by inducing the cholinergic anti-inflammatory pathway, physostigmine reduced the capillary leakage and the leukocyte-endothelial interaction. The treatment with physostigmine in endotoxemia may be of interest for clinical use, and further studies should be performed.
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Dysfunction of hepatic microcirculation during inflammatory stress conditions is associated with overexpression of caveolin 1 (Cav-1) in sinusoidal endothelial cells. Because Cav-1 binds and inhibits eNOS, it was suggested that Cav-1 overexpression inhibits endothelin 1 (ET-1)-mediated eNOS activation after endotoxemia in the liver; however, a causal link between stress-mediated suppression of eNOS and Cav-1 overexpression has not been fully established. We hypothesize that genetic knockout of Cav-1 reverses the LPS-suppressed ET-1-mediated eNOS activation. ⋯ The reversal of LPS inhibition resulted in an increase in ET-1-induced eNOS translocation to the plasma membrane and an augmentation of NO production in the perinuclear region and plasma membrane of Cav-1 KO LSECs. These results showed that genetic knockout of Cav-1 increased basal eNOS activity and at least partially restored ET-1-mediated eNOS translocation and NO production in LSECs after LPS treatment. In conclusion, Cav-1 overexpression is a requirement for decreased eNOS activity in LSECs after endotoxemia.
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Several lines of evidence suggest a biological role for peroxisome proliferator-activated receptor (PPAR) beta/delta in the pathogenesis of a number of diseases. The aim of this study was to investigate the effects of a high-affinity PPAR-beta/delta agonist, GW0742, in a mouse model of carrageenan (CAR)-induced pleurisy. ⋯ Administration of GW0742 (0.3 mg/kg, i.p. bolus) 30 min before and 30 min after a challenge with CAR caused a reduction in all the parameters of inflammation measured. Thus, based on these findings, we propose that a PPAR-beta/delta agonist such as GW0742 may be useful in the treatment of various inflammatory diseases.