Simvastatin attenuates ventilator-induced lung injury in mice.
BACKGROUND
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.
Müller
Holger C
HC
Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. holger.mueller@charite.de
Hellwig
Katharina
K
Rosseau
Simone
S
Tschernig
Thomas
T
Schmiedl
Andreas
A
Gutbier
Birgitt
B
Schmeck
Bernd
B
Hippenstiel
Stefan
S
Peters
Harm
H
Morawietz
Lars
L
Suttorp
Norbert
N
Witzenrath
Martin
M
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001784:Blood Gas Analysis; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000097:blood; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D020545:Respiratory Mucosa / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D019821:Simvastatin / Q000627:therapeutic use*; D055397:Ventilator-Induced Lung Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D000410:Alanine Transaminase