Simvastatin Reduces Endotoxin-Induced Acute Lung Injury by Decreasing Neutrophil Recruitment and Radical Formation

Abstract

IntroductionTreatment 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.MethodsC57Bl/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.ResultsSimvastatin 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.ConclusionSimvastatin 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.

Redox markers and inflammation are differentially affected by atorvastatin, pravastatin or simvastatin administered before endotoxin-induced acute lung injury

“…In our study, we did not observe any change in this marker from prior administration of atorvastatin or simvastatin. Contrasting results were observed by Grommes et al [53] with respect to the simvastatin treatment, which may be explained by the duration of treatment and the administration route.…”

Protective effect of pioglitazone on sepsis-induced intestinal injury in a rodent model

“…In spite of its critical role in mounting host defense reactions, neutrophils can also cause significant tissue damage in inflammatory disease. Neutrophils can secrete destructive elastases and lipid mediators and reactive oxygen species with the capacity to damage both endothelial and epithelial cell function [38,39]. Convincing data have established neutrophil recruitment as a fundamental component in the pathophysiology of sepsis-induced intestinal injury [40,41].…”

Biological Effects of Simvastatin Formulated as pMDI on Pulmonary Epithelial Cells

“…On the other hand, the treatment with LPS as a positive control significantly induces intracellular ROS generation (195%). Although the release of ROS displays important antimicrobial mechanism, overproduction of ROS can lead to tissue damage (48). Hence, SV aerosols generated from the pMDI formulation did not induce the production of inflammatory mediators and oxidative stress, which suggest that inhalation of SV is safe and non-toxic supporting its potential delivery to the lungs as a treatment for chronic lung diseases.…”

“…Following one dose of SV treatment, a 5-fold reduction in ROS production was observed when compared to untreated 'inflamed' cells induced with LPS at 24 and 48 h. These findings was supported by a study by Lee et al (9), were oral SV has been shown to reduce the structural and functional damage to the lungs caused by cigarette smoking by suppressing inflammation and scavenging ROS in rats, suggesting a potential role in the treatment of cigarette smoking-induced COPD. At a molecular level, the inhibition of the small GTPases, specifically Rac1, by SV has been shown to reduce generation of ROS through inactivation of the NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) system (48).…”