NO: More Than Just a Vasodilator in Lung Transplantation

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Abstract
Since the discovery of nitric oxide (NO) in biologic systems a scant 15 years ago, an unprecedented number of studies have explored the role of this molecule in the regulation of the pulmonary circulation. Although numerous models have been employed to study the role of NO in the lung, studies examining the effect of NO on the donor lung pro- vide a unique opportunity to better understand the impor- tance of this molecule in maintaining pulmonary vascular homeostasis. It is hard to imagine a worse injury for the lung to endure than removal from the donor, storage on ice for many hours, and eventual transplantation in the recipi- ent. The donor lung usually receives the majority of the pulmonary blood flow and ventilation immediately after transplantation. This is true even with single lung trans- plantation, because the native lung that remains is often diseased. The result can be severe ischemia-reperfusion (I-R) injury that is often made worse by the high fraction of in- spired oxygen (FiO 2 ) that is needed to oxygenate the pa- tient. Under these circumstances, depletion of any factors important in normal homeostasis of the pulmonary circula- tion can greatly affect the overall survival and function of the donor lung. Previous studies have demonstrated that NO and cGMP levels fall rapidly in the donor lung immediately after harvest (1). Administration of NO or NO donors at the time of lung harvest can greatly improve function and survival of the lung graft (1-4). Recent studies exploring the mechanism of this prophylactic effect, such as the one by Minamoto and coworkers in this issue of AJRCMB , are beginning to illuminate the important role that NO has in maintaining normal function in the injured lung. Cellular Mechanisms Underlying Rejection of Lung Graft Although the mechanisms responsible for early dysfunc- tion and rejection of lung allografts are not yet fully under- stood, there are several events that occur during lung transplantation that are likely to be responsible. These in- clude an increase in pulmonary vascular resistance, in- creased sequestration of polymorphonucelar leukocytes (PMNs), platelet activation, enhanced production of reac- tive oxygen species (ROS), and increased release of in- flammatory cytokines. This is accompanied by increased expression of endothelin-1 (ET-1) (5), a marked decrease in endothelial derived NO production, and lower intracel- lular cGMP levels (1). At the same time, there is increased expression of inducible nitric oxide synthase (iNOS) and apoptosis of pulmonary vascular endothelial and epithelial cells (6). The importance of each of these abnormalities and their relationship with each other is not completely known.