title: Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Anesthesiology, Radboud University Medical Centre, Postbox 9101, Nijmegen, 6500 HB, the Netherlands. willem-jan.schellekens@radboudumc.nl.
authors.forename: Willem-Jan M
authors.initials: WJ
authors.lastname: Schellekens
authors.affiliation: Department of Pulmonary Diseases, Radboud University Medical Centre, Postbox 9101, Nijmegen, 6500 HB, the Netherlands. jeroen.vanhees@radboudumc.nl.
authors.forename: Hieronymus W H
authors.initials: HW
authors.lastname: van Hees
authors.affiliation: Department of Pulmonary Diseases, Radboud University Medical Centre, Postbox 9101, Nijmegen, 6500 HB, the Netherlands. marianne.linkels@radboudumc.nl.
authors.forename: Marianne
authors.initials: M
authors.lastname: Linkels
authors.affiliation: Department of Pulmonary Diseases, Radboud University Medical Centre, Postbox 9101, Nijmegen, 6500 HB, the Netherlands. richard.dekhuijzen@radboudumc.nl.
authors.forename: P N Richard
authors.initials: PN
authors.lastname: Dekhuijzen
authors.affiliation: Department of Anesthesiology, Radboud University Medical Centre, Postbox 9101, Nijmegen, 6500 HB, the Netherlands. gertjan.scheffer@radboudumc.nl.
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Scheffer
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Centre, Postbox 9101, Nijmegen, 6500 HB, the Netherlands. hans.vanderhoeven@radboudumc.nl.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Centre, Postbox 9101, Nijmegen, 6500 HB, the Netherlands. leo.heunks@radboudumc.nl.
authors.forename: Leo M A
authors.initials: LM
authors.lastname: Heunks
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D018925:Chemokines / Q000378:metabolism; D003964:Diaphragm / Q000378:metabolism*; D019446:Endotoxemia / Q000378:metabolism / Q000628:therapy; D006835:Hydrazones / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012121:Respiration, Artificial; D000077464:Simendan
chemical_list: D000447:Aldehydes; D002316:Cardiotonic Agents; D018925:Chemokines; D006835:Hydrazones; D007378:Interleukins; D011724:Pyridazines; D012333:RNA, Messenger; C074302:keratinocyte-derived chemokines; D000077464:Simendan; D019001:Nitric Oxide Synthase; C027576:4-hydroxy-2-nonenal