Simvastatin ameliorates injury in an experimental model of lung ischemia-reperfusion.
OBJECTIVE
Statins are lipid-lowering drugs with anti-inflammatory and antioxidant properties. This study explores the potential of these commonly prescribed agents to ameliorate lung ischemia-reperfusion injury.


METHODS
Left lungs of Long-Evans rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received simvastatin orally (0.5 mg/kg) for 5 days before the experiment. Injury was quantitated in terms of tissue myeloperoxidase content, vascular permeability ((125)I bovine serum albumin extravasation), and bronchoalveolar lavage leukocyte and cytokine content. Changes in nuclear translocation of transcription factors were evaluated by electromobility shift assay. Additional animals received N(G)-nitro-L-arginine methyl ester before ischemia-reperfusion to assess whether inhibition of nitric oxide synthase could reverse simvastatin's protective effects. The presence of nicotinamide adenine dinucleotide phosphate oxidase was also evaluated using enzyme staining both histologically and in native electrophoresis.


RESULTS
Lung vascular permeability was reduced in treated animals by 71% compared with positive controls (P <.001). Administration of N(G)-nitro-L-arginine methyl ester reversed this protection. The protective effects of statin pretreatment correlated with a 68% reduction in tissue myeloperoxidase content (P <.01), marked reductions in bronchoalveolar lavage leukocyte accumulation, and decreased expression of proinflammatory cytokines. Nicotinamide adenine dinucleotide phosphate oxidase expression also decreased with statin treatment.


CONCLUSIONS
In addition to its antioxidant properties, the protective effects of simvastatin are likely mediated by modulation of endothelial nitric oxide synthase. The potential to pretreat recipients of lung transplantation with statins to ameliorate reperfusion injury is promising.
Naidu
Babu V
BV
Division of Cardiothoracic Surgery, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
Woolley
Steven M
SM
Farivar
Alexander S
AS
Thomas
Robert
R
Fraga
Charles
C
Mulligan
Michael S
MS
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects; D002452:Cell Count; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D008171:Lung Diseases / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008955:Models, Cardiovascular; D019255:NADPH Oxidases / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000493:pharmacokinetics / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000187:drug effects; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D019821:Simvastatin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013223:Statistics as Topic; D013997:Time Factors; D014157:Transcription Factors / Q000187:drug effects; D016896:Treatment Outcome
D016207:Cytokines; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D014157:Transcription Factors; D019821:Simvastatin; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D019331:NG-Nitroarginine Methyl Ester