Statins inhibit neutrophil infiltration in skeletal muscle reperfusion injury.
BACKGROUND
Neutrophil infiltration is a major determinant of ischemia-reperfusion injury (IRI). Statins improve endothelial function by elevating nitric oxide synthase activity and inhibiting adhesion molecule expression and may, therefore, inhibit IRI-induced neutrophil extravasation. Although statins are protective against myocardial IRI and stroke, a role for statins in ameliorating skeletal muscle IRI has not yet been confirmed. This study, therefore, addressed the hypothesis that simvastatin would attenuate the severity of tissue damage during skeletal muscle IRI.


METHODS
Rats were administered simvastatin for 6 d before 4 h hind limb ischemia and 24 h reperfusion. Neutrophil infiltration was assessed using myeloperoxidase (MPO) assays and tissue damage by quantitative immunohistochemical analysis of collagen IV. The effect of reducing nitric oxide levels on the severity of IRI was assessed by administering the NOS inhibitor, N-Imino-L-ornithine (L-NIO), before ischemia.


RESULTS
Simvastatin significantly inhibited IRI-induced MPO activity but not collagen degradation in postischemic skeletal muscle. Inhibition of nitric oxide synthase by L-NIO markedly inhibited neutrophil infiltration and protected against IRI-induced collagen degradation. When both simvastatin and L-NIO were administered before IRI, the IRI-induced elevation in MPO activity was completely inhibited. However, paradoxically, simvastatin counteracted the protective effect of L-NIO against IRI-induced collagen IV degradation.


CONCLUSIONS
The inhibition by simvastatin of IRI-induced neutrophil infiltration in skeletal muscle suggests that statins may be a useful therapy to attenuate the severity of IRI but their precise mechanisms of action remains to be determined. Nitric oxide also plays a cytotoxic, rather than protective, role in mediating IRI in this model.
Cowled
Prudence A
PA
Discipline of Surgery, School of Medicine, The University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
Khanna
Achal
A
Laws
Peter E
PE
Field
John B F
JB
Varelias
Antiopi
A
Fitridge
Robert A
RA
D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply*; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009952:Ornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D019821:Simvastatin / Q000494:pharmacology*
D024141:Collagen Type IV; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C065027:N(G)-iminoethylornithine; D019821:Simvastatin; D009952:Ornithine; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9