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J Thorac Cardiovasc Surg 2006;131:969-974
© 2006 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Importance of endothelial nitric oxide synthase for the hypothermic protection of lungs against ischemia-reperfusion injury

Li Zhang, MD, Sanjeev Kumar, BS, Alexander Kaminski, MD, Cornelius Kasch, Christoph Sponholz, MD, Christof Stamm, MD, Yury Ladilov, PhD * , Gustav Steinhoff, MD

Department of Cardiac Surgery, University of Rostock, Rostock, Germany.

Received for publication October 19, 2005; revisions received December 12, 2005; accepted for publication December 16, 2005.

* Address for reprints: Yury Ladilov, PhD, Department of Cardiac Surgery, University of Rostock, Schillingallee 35, 18057 Rostock, Germany. (Email: yury.ladilov{at}med.uni-rostock.de).

OBJECTIVES: The hypothesis that the protective effects of mild hypothermia against the pulmonary ischemia-reperfusion injury are mediated by endothelial nitric oxide synthase was tested.

METHODS: Endothelial nitric oxide synthase knock-out and wild-type mice were sham operated or underwent a 1-hour occlusion of the left pulmonary hilum, followed by 5 hours of reperfusion. Temperature in the left pleural cavity during ischemia was maintained at either 36°C (normothermia) or 32°C (hypothermia). Inflammatory response (myeloperoxidase activity), endothelial barrier function (extravasation of Evans blue–labeled albumin), and endothelial nitric oxide synthase expression and phosphorylation were determined at the end of reperfusion.

RESULTS: After normothermic ischemia both strains had a similar mortality (wild-type, 22.9%; knock-out, 15.4%), which was completely abolished by hypothermia. Endothelial barrier function was disturbed after normothermic ischemia in both wild-type and knock-out mice. Mild hypothermia significantly reduced pulmonary Evans blue extravasation in wild-type mice, but not in knock-out mice. Myeloperoxidase activity increased after normothermic ischemia to the same degree in both strains. This response was significantly attenuated by hypothermia in wild-type mice, but not in knock-out mice. In wild-type mice, endothelial nitric oxide synthase expression and phosphorylation were higher after hypothermic ischemia than after normothermic ischemia. No effect of ischemia on expression of inducible nitric oxide synthase was found in wild-type or knock-out mice.

CONCLUSION: Hypothermic protection against pulmonary ischemia-reperfusion injury is dependent on endothelial nitric oxide synthase and is associated with increased expression and phosphorylation of endothelial nitric oxide synthase.

Abbreviations and Acronyms EB = Evans blue; eNOS = endothelial nitric oxide synthase; iNOS = inducible nitric oxide synthase; nNOS = neuronal nitric oxide synthase; I/R = ischemia/reperfusion; KO = knock-out; MPO = myeloperoxidase; NO = nitric oxide; SEM = standard error of the mean; WT = wild-type






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