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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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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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.
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Randomized Controlled Trial
Efficacy and safety of dopamine versus norepinephrine in the management of septic shock.
The optimum septic shock vasopressor support strategy is currently debated. This study was performed to evaluate the efficacy and safety of norepinephrine (NE) and dopamine (DA) as the initial vasopressor in septic shock patients who were managed with a specific treatment protocol. A prospective, randomized, open-label, clinical trial was used in a medical intensive care unit comparing DA with NE as the initial vasopressor in fluid-resuscitated 252 adult patients with septic shock. ⋯ In this protocol-directed vasopressor support strategy for septic shock, DA and NE were equally effective as initial agents as judged by 28-day mortality rates. However, there were significantly more cardiac arrhythmias with DA treatment. Patients receiving DA should be monitored for the development of cardiac arrhythmias (NCT00604019).