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J Thorac Cardiovasc Surg 2006;132:132-139
© 2006 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Inhaled nitric oxide reduces ischemia-reperfusion injury in rat lungs from non–heart-beating donors

Seiki Takashima, MD a , Giovanna Koukoulis, MD b , Hidetoshi Inokawa, MD a , Mayura Sevala, PhD c , Thomas M. Egan, MD, MSc c , *

a Department of Cancer and Thoracic Surgery (Surgery II), Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
b Department of Cardiothoracic Surgery, University of Pavia, Pavia, Italy
c Division of Cardiothoracic Surgery, Department of Surgery, University of North Carolina, Chapel Hill, NC

Received for publication October 27, 2005; revisions received January 12, 2006; accepted for publication February 21, 2006.

* Address for reprints: Thomas M. Egan, MD, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, CB 7065; 3040 Burnett Womack Building, Chapel Hill, NC 27599-7065. (Email: ltxtme{at}med.unc.edu).

OBJECTIVE: If lungs could be retrieved from non–heart-beating donors, the critical shortage of lungs for transplantation could be alleviated. However, lungs subjected to warm ischemia develop edema when reperfused. We hypothesized that ventilation of rat lungs from non–heart-beating donors with nitric oxide during the period of warm ischemia alone, with reperfusion, or both might reduce ischemia-reperfusion injury.

METHODS: An isolated perfused rat lung model measured the filtration coefficient and accumulation of lung water by the wet/dry weight ratio. Donor rats were euthanized, and then lungs were retrieved immediately after death or 2 or 3 hours postmortem. Lungs retrieved postmortem were either not ventilated or ventilated with 100% oxygen alone or 40 ppm nitric oxide in oxygen. In the circuit, lungs were ventilated with alveolar gas with or without 40 ppm nitric oxide.

RESULTS: Nitric oxide administration to the non–heart-beating donor or in the perfusion circuit reduced filtration coefficient and wet/dry weight ratio. Lungs retrieved 2 hours postmortem ventilated with nitric oxide or treated with nitric oxide on reperfusion had filtration coefficients and wet/dry weight ratios similar to those of lungs retrieved immediately after death. Nitric oxide was most beneficial when administered both during warm ischemia and at reperfusion in lungs retrieved 3 hours postmortem. Nitric oxide administration in the circuit was associated with increased lung levels of lung cyclic guanosine monophosphate, determined by enzyme-linked immunosorbent assay.

CONCLUSIONS: Administration of nitric oxide to non–heart-beating donors during warm ischemia and with reperfusion might facilitate transplantation of lungs from non–heart-beating donors by reducing ischemia-reperfusion injury and capillary leak.

Abbreviations and Acronyms cAMP = cyclic adenasine monophosphate; cGMP = guanosine 3', 5' monophosphate; IPRLM = isolated perfused rat lung model; IRI = ischemia-reperfusion injury; Kfc = filtration coefficient; NHBD = non–heart-beating donor; NO = nitric oxide; NO-D = inhaled NO during the ischemic interval alone; NO-D+R = inhaled NO during both the ischemic interval and reperfusion; NO-R = inhaled NO during reperfusion alone; NTG = nitroglycerin; PEEP = positive end-expiratory pressure; Ppv = pulmonary venous pressure; W/D = wet/dry weight ratio




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