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Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice

INTRODUCTION: Controlled mechanical ventilation and endotoxemia are associated with diaphragm muscle atrophy and dysfunction. Oxidative stress and activation of inflammatory pathways are involved in the pathogenesis of diaphragmatic dysfunction. Levosimendan, a cardiac inotrope, has been reported to...

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Autores principales: Schellekens, Willem-Jan M, van Hees, Hieronymus WH, Linkels, Marianne, Dekhuijzen, PN Richard, Scheffer, Gert Jan, van der Hoeven, Johannes G, Heunks, Leo MA
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355991/
https://www.ncbi.nlm.nih.gov/pubmed/25888356
http://dx.doi.org/10.1186/s13054-015-0798-8
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author Schellekens, Willem-Jan M
van Hees, Hieronymus WH
Linkels, Marianne
Dekhuijzen, PN Richard
Scheffer, Gert Jan
van der Hoeven, Johannes G
Heunks, Leo MA
author_facet Schellekens, Willem-Jan M
van Hees, Hieronymus WH
Linkels, Marianne
Dekhuijzen, PN Richard
Scheffer, Gert Jan
van der Hoeven, Johannes G
Heunks, Leo MA
author_sort Schellekens, Willem-Jan M
collection PubMed
description INTRODUCTION: Controlled mechanical ventilation and endotoxemia are associated with diaphragm muscle atrophy and dysfunction. Oxidative stress and activation of inflammatory pathways are involved in the pathogenesis of diaphragmatic dysfunction. Levosimendan, a cardiac inotrope, has been reported to possess anti-oxidative and anti-inflammatory properties. The aim of the present study was to investigate the effects of levosimendan on markers for diaphragm nitrosative and oxidative stress, inflammation and proteolysis in a mouse model of endotoxemia and mechanical ventilation. METHODS: Three groups were studied: (1) unventilated mice (CON, n =8), (2) mechanically ventilated endotoxemic mice (MV LPS, n =17) and (3) mechanically ventilated endotoxemic mice treated with levosimendan (MV LPS + L, n =17). Immediately after anesthesia (CON) or after 8 hours of mechanical ventilation, blood and diaphragm muscle were harvested for biochemical analysis. RESULTS: Mechanical ventilation and endotoxemia increased expression of inducible nitric oxide synthase (iNOS) mRNA and cytokine levels of interleukin (IL)-1β, IL-6 and keratinocyte-derived chemokine, and decreased IL-10, in the diaphragm; however, they had no effect on protein nitrosylation and 4-hydroxy-2-nonenal protein concentrations. Levosimendan decreased nitrosylated proteins by 10% (P <0.05) and 4-hydroxy-2-nonenal protein concentrations by 13% (P <0.05), but it augmented the rise of iNOS mRNA by 47% (P <0.05). Levosimendan did not affect the inflammatory response in the diaphragm induced by mechanical ventilation and endotoxemia. CONCLUSIONS: Mechanical ventilation in combination with endotoxemia results in systemic and diaphragmatic inflammation. Levosimendan partly decreased markers of nitrosative and oxidative stress, but did not affect the inflammatory response.
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spelling pubmed-43559912015-03-12 Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice Schellekens, Willem-Jan M van Hees, Hieronymus WH Linkels, Marianne Dekhuijzen, PN Richard Scheffer, Gert Jan van der Hoeven, Johannes G Heunks, Leo MA Crit Care Research INTRODUCTION: Controlled mechanical ventilation and endotoxemia are associated with diaphragm muscle atrophy and dysfunction. Oxidative stress and activation of inflammatory pathways are involved in the pathogenesis of diaphragmatic dysfunction. Levosimendan, a cardiac inotrope, has been reported to possess anti-oxidative and anti-inflammatory properties. The aim of the present study was to investigate the effects of levosimendan on markers for diaphragm nitrosative and oxidative stress, inflammation and proteolysis in a mouse model of endotoxemia and mechanical ventilation. METHODS: Three groups were studied: (1) unventilated mice (CON, n =8), (2) mechanically ventilated endotoxemic mice (MV LPS, n =17) and (3) mechanically ventilated endotoxemic mice treated with levosimendan (MV LPS + L, n =17). Immediately after anesthesia (CON) or after 8 hours of mechanical ventilation, blood and diaphragm muscle were harvested for biochemical analysis. RESULTS: Mechanical ventilation and endotoxemia increased expression of inducible nitric oxide synthase (iNOS) mRNA and cytokine levels of interleukin (IL)-1β, IL-6 and keratinocyte-derived chemokine, and decreased IL-10, in the diaphragm; however, they had no effect on protein nitrosylation and 4-hydroxy-2-nonenal protein concentrations. Levosimendan decreased nitrosylated proteins by 10% (P <0.05) and 4-hydroxy-2-nonenal protein concentrations by 13% (P <0.05), but it augmented the rise of iNOS mRNA by 47% (P <0.05). Levosimendan did not affect the inflammatory response in the diaphragm induced by mechanical ventilation and endotoxemia. CONCLUSIONS: Mechanical ventilation in combination with endotoxemia results in systemic and diaphragmatic inflammation. Levosimendan partly decreased markers of nitrosative and oxidative stress, but did not affect the inflammatory response. BioMed Central 2015-03-02 2015 /pmc/articles/PMC4355991/ /pubmed/25888356 http://dx.doi.org/10.1186/s13054-015-0798-8 Text en © Schellekens et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Schellekens, Willem-Jan M
van Hees, Hieronymus WH
Linkels, Marianne
Dekhuijzen, PN Richard
Scheffer, Gert Jan
van der Hoeven, Johannes G
Heunks, Leo MA
Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice
title Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice
title_full Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice
title_fullStr Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice
title_full_unstemmed Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice
title_short Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice
title_sort levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355991/
https://www.ncbi.nlm.nih.gov/pubmed/25888356
http://dx.doi.org/10.1186/s13054-015-0798-8
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