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

Abstract

IntroductionControlled 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.MethodsThree 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.ResultsMechanical 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.ConclusionsMechanical 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.

Late Therapeutic Intervention with Antibiotics and Fluid Resuscitation Allows for a Prolonged Disease Course with High Survival in a Severe Murine Model of Sepsis

“…In this study we did not include ventilatory support, but predict that it would be beneficial not only for clinical relevance but also for survival. However, we aimed to develop a therapeutic strategy which could be adopted by many laboratory groups, and prolonged murine ventilation is a technically challenging technique which requires specialized equipment and also adds variables (such as prolonged use of anesthesia (33, 34)) to the experiment which is often undesirable, but would be worthwhile to include in future experiments.…”

Diaphragm Atrophy and Weakness in the Absence of Mitochondrial Dysfunction in the Critically Ill

“…Thus, mitochondrial dysfunction and oxidative stress do not play a causative role in the development of atrophy and contractile weakness of the diaphragm in critically ill patients. and dynamics, and oxidative stress were measured by Western blotting, and described previously (29)(30)(31)(32)(33)(34). Nuclear factor erythroid 2-related factor 2 (Nrf2) was measured by real-time PCR, as described previously (30).…”

Levosimendan prevents bronchoconstriction and adverse respiratory tissue mechanical changes in rabbits

“…Another possible limitation of our impedance data is related to the measurement of the total respiratory system, including pulmonary and chest wall compartments (43). Because rabbits were under complete muscle relaxation during the entire protocol, the possible effects of levosimendan on the diaphragm and/or on the chest wall muscles (10,40,45) were completely absent. Therefore, the changes in the tissue mechanical parameters were of pulmonary origin.…”