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J Thorac Cardiovasc Surg 2003;126:482-489
© 2003 The American Association for Thoracic Surgery

Cardiothoracic transplantation

Simvastatin ameliorates injury in an experimental model of lung ischemia-reperfusion

^a Division of Cardiothoracic Surgery, University of Washington, Seattle, Wash, USA

Read at the Twenty-seventh Annual Meeting of The Western Thoracic Surgical Association, Big Sky, Mont, June 19-22, 2002.

Received for publication June 28, 2002; revisions received August 19, 2002; revisions received December 13, 2002; accepted for publication January 14, 2003.

^* Address for reprints: Michael S. Mulligan, MD, FACS, Box 356310, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, USA
msmmd{at}u.washington.edu

OBJECTIVES: 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 (¹²⁵I 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.

CONCLUSION: 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.

Key Words: 9

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