Simvastatin reduces endotoxin-induced acute lung injury by decreasing neutrophil recruitment and radical formation.
BACKGROUND
Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. As simvastatin exerts protective effects in inflammatory diseases we explored its effects on development of ALI and due to the importance of neutrophils in ALI also on neutrophil effector functions.


METHODS
C57Bl/6 mice were exposed to aerosolized LPS (500 µg/ml) for 30 min. The count of alveolar, interstitial, and intravasal neutrophils were assessed 4 h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and albumin content in the BAL fluid. In vitro, we analyzed the effect of simvastatin on neutrophil adhesion, degranulation, apoptosis, and formation of reactive oxygen species. To monitor effects of simvastatin on bacterial clearance we performed phagocytosis and bacterial killing studies in vitro as well as sepsis experiments in mice.


RESULTS
Simvastatin treatment before and after onset of ALI reduces neutrophil influx into the lung as well as lung permeability indicating the protective role of simvastatin in ALI. Moreover, simvastatin reduces the formation of ROS species and adhesion of neutrophils without affecting apoptosis, bacterial phagocytosis and bacterial clearance.


CONCLUSIONS
Simvastatin reduces recruitment and activation of neutrophils hereby protecting from LPS-induced ALI. Our results imply a potential role for statins in the management of ALI.
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen, Aachen, Germany. jgrommes@ukaachen.de
Jochen
J
Grommes
Santosh
S
Vijayan
Maik
M
Drechsler
Helene
H
Hartwig
Matthias
M
Mörgelin
Rolf
R
Dembinski
Michael
M
Jacobs
Thomas Andreas
TA
Koeppel
Marcel
M
Binnebösel
Christian
C
Weber
Oliver
O
Soehnlein
D055371:Acute Lung Injury / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology; D000336:Aerosols / Q000633:toxicity; D000418:Albumins / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002448:Cell Adhesion / Q000187:drug effects; D004731:Endotoxins / Q000633:toxicity*; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*
D000336:Aerosols; D000418:Albumins; D004731:Endotoxins; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D019821:Simvastatin; D016650:Fluorescein-5-isothiocyanate