Simvastatin plus nitric oxide synthase inhibition modulates remote organ damage following skeletal muscle ischemia-reperfusion injury.
Ischemia-reperfusion injury (IRI) to the lower extremities causes both local damage and serious dysfunction to remote organs, including lungs and kidneys. However, effective therapies are not available. This study aims to determine if simvastatin reduced the severity of remote damage following IRI.


METHODS
Rats were given simvastatin before hind limb IRI. Lung and kidney tissues were assessed for neutrophil infiltration using myeloperoxidase assays and basement membrane damage by quantitative immunohistochemical measurement of collagen IV. The effect of nitric oxide synthase (NOS) inhibition on remote damage after IRI and simvastatin was assessed using the NOS inhibitor, L-NIO.


RESULTS
Simvastatin (2 mg/kg) protected kidneys against IRI-induced neutrophil infiltration. Simvastatin also inhibited the IRI-induced activation of MMP-9 in the lungs. However, paradoxically, simvastatin exacerbated IRI-induced neutrophil infiltration into the lungs. IRI induced collagen IV degradation in the lungs but not in the kidneys. The degree of collagen breakdown in the lungs was significantly ameliorated by 2 mg/kg simvastatin. NOS inhibition markedly protected both the lungs and the kidneys against IRI-induced neutrophil infiltration but did not alter collagen IV degradation. Administration of simvastatin to L-Nio-treated animals enhanced the degree of protection against IRI-induced neutrophil infiltration in the kidneys but not in the lungs.


CONCLUSIONS
Simvastatin protects against remote IRI-induced damage in the lungs and kidneys, suggesting statins may reduce the severity of IRI during major vascular surgery.
Discipline of Surgery, The University of Adelaide, Australia.
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PA
Cowled
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Khanna
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Laws
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JB
Field
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Fitridge
D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics; D009952:Ornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy*; D019821:Simvastatin / Q000494:pharmacology*
D024141:Collagen Type IV; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; C065027:N(G)-iminoethylornithine; D019821:Simvastatin; D009952:Ornithine; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D020780:Matrix Metalloproteinase 9