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01.08.2010 | Research | Ausgabe 4/2010 Open Access

Critical Care 4/2010

Simvastatin attenuates ventilator-induced lung injury in mice

Zeitschrift:
Critical Care > Ausgabe 4/2010
Autoren:
Holger C Müller, Katharina Hellwig, Simone Rosseau, Thomas Tschernig, Andreas Schmiedl, Birgitt Gutbier, Bernd Schmeck, Stefan Hippenstiel, Harm Peters, Lars Morawietz, Norbert Suttorp, Martin Witzenrath
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​cc9209) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

HCM designed, coordinated and supervised all experiments, analysed the data and drafted the manuscript. KH and BG carried out the animal experiments and performed flow cytometry experiments. SR contributed to the design of the experiments and drafted the manuscript. TT and AS performed electron microscopy and were responsible for image analysis. BS and SH carried out multiplex array experiments while HP performed cystatin C analysis and NS participated in drafting the manuscript. MW participated in the study design and drafted the manuscript.

Abstract

Introduction

Mechanical ventilation (MV) is a life saving intervention in acute respiratory failure without alternative. However, particularly in pre-injured lungs, even protective ventilation strategies may evoke ventilator-induced lung injury (VILI), which is characterized by pulmonary inflammation and vascular leakage. Adjuvant pharmacologic strategies in addition to lung protective ventilation to attenuate VILI are lacking. Simvastatin exhibited anti-inflammatory and endothelial barrier stabilizing properties in vitro and in vivo.

Methods

Mice were ventilated (12 ml/kg; six hours) and subjected to simvastatin (20 mg/kg) or sham treatment. Pulmonary microvascular leakage, oxygenation, pulmonary and systemic neutrophil and monocyte counts and cytokine release in lung and blood plasma were assessed. Further, lung tissue was analyzed by electron microscopy.

Results

Mechanical ventilation induced VILI, displayed by increased pulmonary microvascular leakage and endothelial injury, pulmonary recruitment of neutrophils and Gr-1high monocytes, and by liberation of inflammatory cytokines in the lungs. Further, VILI associated systemic inflammation characterized by blood leukocytosis and elevated plasma cytokines was observed. Simvastatin treatment limited pulmonary endothelial injury, attenuated pulmonary hyperpermeability, prevented the recruitment of leukocytes to the lung, reduced pulmonary cytokine levels and improved oxygenation in mechanically ventilated mice.

Conclusions

High-dose simvastatin attenuated VILI in mice by reducing MV-induced pulmonary inflammation and hyperpermeability.
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