Browsing Artikler, rapporter og annet (klinisk medisin) by Author "Andreasen, Thomas"
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Browsing Artikler, rapporter og annet (klinisk medisin) by Author "Andreasen, Thomas"
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Kuklin, Vladimir N.; Sovershaev, Mikhail; Andreasen, Thomas; Skogen, Vegard; Ytrehus, Kirsti; Bjertnæs, Lars J. (Journal article; Tidsskriftartikkel; Peer reviewed, 18-Oct-2005)[+][-]
Abstract: Introduction: We recently demonstrated that the non-selective endothelin-1 (ET-1) receptor blocker tezosentan antagonizes ovine acute lung injury (ALI) following infusion of endotoxin or ET-1 by reducing the enhanced lung microvascular pressure, although we could not exclude the possibility of a simultaneous decline in microvascular permeability. In the present study, our aim was to find out if tezosentan reverses the rise in microvascular filtration coefficient (Kfc) in rat lungs that have been isolated and perfused 12 h after cecum ligation and puncture (CLP) or infusion of ET-1. Methods: Wistar rats (n = 42) were subjected to CLP. Postoperatively, rats were randomized to a CLP group (n = 7) and a CLP + tezosentan group (n = 7); the latter received tezosentan 30 mg/kg. A sham-operated group (n = 5) underwent laparotomy without CLP. Twelve hours postoperatively, the lungs were isolated and perfused with blood from similarly treated rats that also were used to assess plasma concentration of ET-1 and protein kinase Cα (PKCα) in lung tissue. Additionally, isolated blood perfused lungs from healthy rats were randomized to a control group (n = 8), an ET-1 group (n = 7) subjected to pulmonary arterial injection of ET-1 10 nM, and an ET-1 + tezosentan group (n = 7) that received tezosentan 30 mg/kg. All lung preparations received papaverine 0.1 μg/kg added to the perfusate for vasoplegia. Pulmonary hemodynamic variables, Kfc and lung compliance (CL) were assessed. Results: After CLP, the plasma concentration of ET-1 increased. Papaverine abolished the vasoconstrictor response to ET-1 and the pulmonary vascular pressures remained close to baseline throughout the experiments. Both CLP and injection of ET-1 caused significant changes in Kfc and CL that were prevented in tezosentan-treated rats. Compared to sham-operated animals, CLP increased the content of PKCα by 50% and 70% in the cytosolic and the membrane fractions of lung tissue homogenates, respectively. Tezosentan prevented the upregulation of PKCα in the membrane fraction. Conclusion: In rat lungs isolated and perfused after CLP, tezosentan precludes both the increase in Kfc and the upregulation of PKCα in the membrane fraction of lung tissue. URI: http://hdl.handle.net/10037/1122 File(s) in this item: 1
article.pdf (461.8Kb) -
Ingebretsen, Ole C.; Kuklin, Vladimir N.; Kirov, Mikhail Y.; Sovershaev, Mikhail; Andreasen, Thomas; Ytrehus, Kirsti; Bjertnæs, Lars J. (Journal article; Tidsskriftartikkel; Peer reviewed, 04-Mar-2005)[+][-]
Abstract: Introduction: Studies in vitro reveal that endothelin-1 (ET-1) activates the α isoform of protein kinase C (PKC-α) in cultures of endothelial cells, thereby deranging cellular integrity. Sepsis and endotoxemia are associated with increased plasma concentrations of ET-1 that induce acute lung injury (ALI). We recently reported that non-selective ET-1 receptor blockade attenuates ALI in sheep by reducing the endotoxin-induced increase in extravascular lung water index (EVLWI). The aim of this study was to find out whether this attenuation is associated with reduced translocation of PKC-α from the cytosolic to the membrane fraction of lung tissue homogenate. Methods: Seventeen awake, instrumented sheep were randomly assigned to a sham-operated group (n = 3), a lipopolysaccharide (LPS) group (n = 7) receiving an intravenous infusion of Escherichia coli 15 ng/kg per min for 24 hours, and a tezosentan group (n = 7) subjected to LPS and, from 4 hours, an intravenous injection of tezosentan 3 mg/kg followed by infusion at 1 mg/kg per hour for the reminder of the experiment. Pulmonary micro-occlusion pressure (Pmo), EVLWI, plasma concentrations of ET-1, tumor necrosis factor-a (TNF-a), and interleukin-8 (IL-8) were determined every 4 hours. Western blotting was used to assess PKC-α. Results: In non-treated sheep a positive correlation was found between the plasma concentration of ET-1 and Pmo in the late phase of endotoxemia (12 to 24 hours). A positive correlation was also noticed between Pmo and EVLWI in the LPS and the LPS plus tezosentan groups, although the latter was significantly reduced in comparison with LPS alone. In both endotoxemic groups, plasma concentrations of ET-1, TNF-α, and IL-8 increased. In the LPS group, the cytosolic fraction of PKC-α decreased by 75% whereas the membrane fraction increased by 40% in comparison with the sham-operated animals. Tezosentan completely prevented the changes in PKC-α in both the cytosolic and the membrane fractions, concomitantly causing a further increase in the plasma concentrations of ET-1, TNF-α, and IL-8. Conclusion: In endotoxemic sheep, ET-1 receptor blockade alleviates lung injury as assessed by a decrease in EVLWI paralleled by a reduction in Pmo and the prevention of activation of PKC-α. URI: http://hdl.handle.net/10037/1128 File(s) in this item: 1
article.pdf (331.0Kb)
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