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© 2014 Direct One Communications, Inc. All rights reserved. 1 The Role of Nitric Oxide in Solid-Organ Transplantation Imran Javed, MD University of Washington Medical Center, Seattle, Washington A REPORT FROM THE 2014 WORLD TRANSPLANT CONGRESS
© 2014 Direct One Communications, Inc. All rights reserved. 2 Ischemic Reperfusion Injury Within minutes following reperfusion of the ischemic vasculature of a transplanted organ, the microcirculation endures endothelial dysfunction, characterized by a loss in basal and agonist-mediated nitric oxide produced by the vascular endothelium. The loss of nitric oxide results in upregulation of cell adhesion molecules (CAMs), particularly P-selectin, following reperfusion. A marked degree of leukocyte adherence involving neutrophils (in particular) occurs following reperfusion, leasing to neutrophil infiltration of the underlying tissue. de Groot H, Rauen U. Transplant Proc. 2007;39:481; Gourdin M, Dubois P, in Artery Bypass (InTech; 2013)
© 2014 Direct One Communications, Inc. All rights reserved. 3 Ischemic Reperfusion Injury continued Cellular response in ischemic reperfusion injury Gourdin M, Dubois P, in Aronow WS, ed. Artery Bypass (InTech; 2013)
© 2014 Direct One Communications, Inc. All rights reserved. 4 Ischemic Reperfusion Injury continued The infiltration of neutrophils leads to reperfusion injury (ie, necrosis) that is significant after 3 hours and becomes profound after 4½ hours. The degree of ischemic reperfusion injury (IRI) is directly associated with the ischemia time and inversely proportion to the size of the allograft. IRI reduces the regenerative capabilities of allograft, which directly impacts morbidity, mortality, and long-term patient outcomes. IRI also limits the use of marginal grafts, particularly when tissues from extended-criteria donors are used. Kr ü ger B et al. Proc Natl Acad Sci U S A. 2009;106:3390; Zhai Y et al. J Immunol. 2004;173:7115
© 2014 Direct One Communications, Inc. All rights reserved. 5 Physiologic Role of Nitric Oxide Nitric oxide is a powerful vasodilator with a half-life of just a few seconds in the blood. Nitric oxide synthetase inhibits cell death, neutrophil migration and activation, platelet aggregation and adhesion, CAMs, and release of vasoconstrictors and growth factors. Nitric oxide works as an antioxidant and anti- inflammatory agent, inactivates superoxides, and imparts beneficial effects on cell signaling and inhibition of nuclear proteins, thereby protecting against ischemic reperfusion injury. Phillips L et al. J Invest Surg. 2009;22:46
© 2014 Direct One Communications, Inc. All rights reserved. 6 Inhaled Nitric Oxide (iNO) iNO is a selective pulmonary vasodilator. Administration of iNO reduces the need for extracorporeal membrane oxygenation in infants who have persistent pulmonary hypertension. More recently, iNO is being tested for benefits in patients with such pulmonary pathologies as acute respiratory distress syndrome, where it acutely improves hypoxemia. However, these short-term benefits of iNO have not been shown conclusively to outweigh its potential toxicities. Weinberger B et al. Am J Respir Crit Care Med. 1998;158:931
© 2014 Direct One Communications, Inc. All rights reserved. 7 Inhaled Nitric Oxide (iNO) continued High-dose iNO reduces surfactant function in the lung and also acts as a pulmonary irritant, causing activation of pulmonary macrophages and oxidative injury to the pulmonary epithelium. At concentrations exceeding 8–100 ppm, iNO has proinflammatory and pro-oxidant effects, increasing macrophage production of tumor necrosis factor- , interleukin-1, and reactive oxygen species. In mice, iNO has been shown to protect against myocardial IRI, decreasing infarction size and improving left ventricular function. Weinberger B et al. Pharmacol Ther. 1999;84:401; Hataishi R et al. Am J Physiol Heart Circ Physiol. 2006;291:H379
© 2014 Direct One Communications, Inc. All rights reserved. 8 Inhaled Nitric Oxide (iNO) continued In cats, iNO inhibits inflammation and reduces mesenteric ischemic reperfusion injury. In clinical studies, iNO has been shown to increase blood flow in the forearm during nitric oxide deficiency and significantly reduce inflammation in tourniquet-induced lower extremity ischemia. iNO also has been shown to accelerate restoration of liver function in adults following orthotopic liver transplantation, lowering serum transaminase levels, reducing complications at 9 months post transplant, and improving graft function. Fox-Robichaud A et al. J Clin Invest. 1998;101:2497; Cardillo C et al. Hypertension. 2000; 35:1237; Mathru M et al. Anesthesiology. 2007;106:275; Lang JD Jr et al. J Clin Invest. 2007;117:2583; Lang JD Jr et al. PLoS One. 2014;9:e86053.
© 2014 Direct One Communications, Inc. All rights reserved. 9 Pharmacology of Nitric Oxide Nitric oxide acts on soluble guanylyl cyclase, resulting in increased levels of cyclic GMP in pulmonary smooth muscle cells. Nitric oxide also may regulate pulmonary vasodilation by direct activation of potassium channels or by modulation of the expression and activity of angiotensin II receptors. After inhalation, nitric oxide diffuses into the bloodstream and rapidly reacts with oxyhemoglobin to form methemoglobin and nitrate and with deoxyhemoglobin to form iron-nitrosyl-hemoglobin The half-life of nitric oxide is ~ 2 ms in whole blood. Gross SS. Nature. 2001;409:577
© 2014 Direct One Communications, Inc. All rights reserved. 10 Pharmacology of Nitric Oxide continued Reactions of nitric oxide (NO) in red blood cells Gross SS. Nature. 2001;409:577
© 2014 Direct One Communications, Inc. All rights reserved. 11 Pharmacology of Nitric Oxide continued In the blood, nitric oxide is converted to nitrite. Following inhalation of 80 ppm of iNO, nitrite levels rise significantly in serum and cerebrospinal fluid, and nitrate blood levels increase fourfold. Almost 70% of iNO is excreted within 48 hours as nitrate in the urine. Nitrite has a protective role in ischemic/reperfusion studies in animal models. In humans, nitrite has proven beneficial in the setting of crush injury/ischemia reperfusion. Ibrahim YI et al. J Pediatr. 2012;160:245; Duranski MR et al. J Clin Invest. 2005;115:1232; Wennmalm A et al. Circ Res. 1993;73:1121
© 2014 Direct One Communications, Inc. All rights reserved. 12 Pharmacology of Nitric Oxide continued Nitrite decreases in vivo ischemic-reperfusion injury of liver transplants in a U-shaped, dose-dependent manner. Duranski MR et al. J Clin Invest. 2005;115:1232
© 2014 Direct One Communications, Inc. All rights reserved. 13 iNO in Lung Transplantation IRI is the major cause of primary graft dysfunction following lung transplantation. Mild IRI is seen in more than 95% of lung-transplant recipients; in about 30% of patients receiving a lung transplant, IRI is severe. Administration of iNO after lung transplantation improves gas-exchange properties and selective pulmonary vasodilation, decreases pulmonary vascular resistance, and improves ventilation perfusion mismatch. Although improved graft function is not always seen, an improvement in hemodynamics may be expected. Belperio JA et al. J Immunol. 2005;175:1631; Pasero D et al. Minerva Anesthesiol. 2010;76:353; Tavare AN, Tsakok T. Interact Cardiovasc Thorac Surg. 2011;13:516; Yerebakan C et al. J Card Surg. 2009;24:269
© 2014 Direct One Communications, Inc. All rights reserved. 14 iNO in Lung Transplantation continued Outcomes of studies of iNO in human lung transplantation are limited because of small sample size, duration and time of initiation of iNO therapy, and iNO dosing. In one study, 29 lung-transplant recipients treated with iNO had a significantly lower incidence of primary graft dysfunction compared with 20 untreated control patients (17% vs 45%). A significant difference also was observed between the iNO-treated and control patients when levels of IL-6, IL-8, and IL-10 were assessed in blood and bronchoalveolar lavage fluid at 12 and 24 hours. Moreno I et al. Transplant Proc. 2009;41:2210
© 2014 Direct One Communications, Inc. All rights reserved. 15 Conclusion iNO is a well-established modality in the treatment of premature infants and patients with acute lung injury and acute respiratory distress syndrome. In the setting of IRI associated with solid-organ transplantation, however, its promise is still largely untested. More studies are needed to explore the multifactorial and complex mechanisms of action of iNO in lung and other solid-organ transplant recipients and its potential therapeutic value in these patients.
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