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

Schellekens WJ, van Hees HW, Linkels M, Dekhuijzen PN, Scheffer GJ, van der Hoeven JG, Heunks LM - Crit Care (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Radboud University Medical Centre, Postbox 9101, Nijmegen, 6500 HB, the Netherlands. willem-jan.schellekens@radboudumc.nl.

ABSTRACT

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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Related in: MedlinePlus

Mean arterial pressure during 8 hours of mechanical ventilation. LPS, Lipopolysaccharide; MV LPS, Mechanically ventilated endotoxemic mice; MV LPS + L, Mechanically ventilated endotoxemic mice treated with levosimendan.
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Fig1: Mean arterial pressure during 8 hours of mechanical ventilation. LPS, Lipopolysaccharide; MV LPS, Mechanically ventilated endotoxemic mice; MV LPS + L, Mechanically ventilated endotoxemic mice treated with levosimendan.

Mentions: Blood pressure decreased progressively in both groups during 8 hours of MV (Figure 1) (P =0.09), despite volume therapy (0.3 ml/hr). Blood gas analysis results at the end of the experiments are shown in Table 1. The alveolar-arterial (A-a) oxygen gradient was high after 8 hours of MV in both groups (Table 1). During 8 hours of MV, 30% of the animals in the MV LPS group died (n =5: respectively, 4 hours, 5 hours and 5½ hours, and two mice died after 6 hours of MV). In the levosimendan-treated group, 12% (n =2) died before the end of the planned duration of MV (after 5 and 7½ hours of ventilation, respectively; P =0.2 between groups). Animals that did not survive until the end of the study were excluded from further biochemical analysis. Accordingly, 8 CON mice, 12 MV LPS mice and 14 MV LPS + L mice were included for biochemical analysis.Figure 1


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

Schellekens WJ, van Hees HW, Linkels M, Dekhuijzen PN, Scheffer GJ, van der Hoeven JG, Heunks LM - Crit Care (2015)

Mean arterial pressure during 8 hours of mechanical ventilation. LPS, Lipopolysaccharide; MV LPS, Mechanically ventilated endotoxemic mice; MV LPS + L, Mechanically ventilated endotoxemic mice treated with levosimendan.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4355991&req=5

Fig1: Mean arterial pressure during 8 hours of mechanical ventilation. LPS, Lipopolysaccharide; MV LPS, Mechanically ventilated endotoxemic mice; MV LPS + L, Mechanically ventilated endotoxemic mice treated with levosimendan.
Mentions: Blood pressure decreased progressively in both groups during 8 hours of MV (Figure 1) (P =0.09), despite volume therapy (0.3 ml/hr). Blood gas analysis results at the end of the experiments are shown in Table 1. The alveolar-arterial (A-a) oxygen gradient was high after 8 hours of MV in both groups (Table 1). During 8 hours of MV, 30% of the animals in the MV LPS group died (n =5: respectively, 4 hours, 5 hours and 5½ hours, and two mice died after 6 hours of MV). In the levosimendan-treated group, 12% (n =2) died before the end of the planned duration of MV (after 5 and 7½ hours of ventilation, respectively; P =0.2 between groups). Animals that did not survive until the end of the study were excluded from further biochemical analysis. Accordingly, 8 CON mice, 12 MV LPS mice and 14 MV LPS + L mice were included for biochemical analysis.Figure 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Radboud University Medical Centre, Postbox 9101, Nijmegen, 6500 HB, the Netherlands. willem-jan.schellekens@radboudumc.nl.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus