ANALYSIS
AND
COMMENTARY
Hydrogen in Lung ReconditioningVMore Than Just Inflation John Dark
rgan perfusion, with us since the days of Carrel and Lindbergh, is coming into vogue across all of transplantation. As we expand the use of organs from donation after cardio-circulatory death donors, and increasingly appreciate the scope for damage after brain stem death, perfusion of isolated organs is being seen as a solution to some of the problems of both organ number and quality. The lung has lead the way, perhaps not only because it is vulnerability to the sequelae of brain death (1) but also because of its unique suitability to donation after circulatory death. Cellular metabolism of the lung can be maintained by simple inflation, in the absence of a circulation, probably for several hours (2). So ischemia is less an issue than assessment of function. In a life-supporting organ, reliable assessment is crucial. Ex vivo lung perfusion (EVLP) was introduced by Steen et al. (3) specifically for DCD lung assessmentVhis first case involved a Maastricht category ll donor and had excellent function after lung quality could be measured in an objective fashion. Subsequently, it was realized by the group in Lund, then workers in Toronto and finally in centers around the world, that EVLP was also a vehicle to improve, or recondition, lungs initially below the standard needed for primary transplantation (4). The most important step was that of Steen demonstrating, in contrast to previous experience, that endothelial integrity could be maintained. Key ingredients were the absence of white cells, platelets, and complement, a hyperosmolar solution and a perfusion approach which minimized shear stress. So great was the difference from the previous experience of inevitable and progressive pulmonary edema that it has been widely assumed that the circuit did no harm at all to the lung. However, this is a naive viewVas the landmark study by Noda and colleagues from the University of Pittsburgh has demonstrated.
O
The author declares no funding or conflicts of interest. Institute of Cellular Medicine, Newcastle University. Address correspondence to: John Dark, Institute of Cellular Medicine Newcastle University, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom. E-mail: [email protected] Received 6 May 2014. Accepted 8 May 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9805-497 DOI: 10.1097/TP.0000000000000311
Transplantation
& Volume 98, Number 5, September 15, 2014
Using a rat model, they showed that EVLP was associated with a proinflammatory environment. They went on to demonstrate that inhaled hydrogen would ameliorate this state, and the effect translated into better function after transplant of the lungs, and a strikingly low inflammatory cell infiltrate in those transplants. The effects of hydrogen as an antioxidant, anti-inflammatory, and antiapoptotic agent are only just now being realized, and this is the first study of the molecule in EVLP. There were additional effects on the levels of lactate which are more difficult to explain. Glucose metabolism in the lung produces lactate, which is then consumed, in the intact animal, by muscle, kidney, and liver. In the artificial setting of isolated lung perfusion, lactate accumulates just as glucose disappears. Although it generates metabolic acidosis, and high lactate has theoretical disadvantageous effects on some aspects of neutrophil function, studies such as those by Koike at al. in Toronto have shown no bad effect on the lung (5). However, hydrogen is clearly having some effect at mitochondrial level, perhaps through the heme-oxygenase-1 pathway. That this is of potential real benefit, regardless of mechanism, is shown by improved adenosine triphospate levels in the lungs exposed to hydrogen. It is a pity that lactate-to-pyruvate ratios, a simple way of looking at some aspects of lactate production, were not measured. The lung has huge advantages, in that the beneficial agent, hydrogen here, can be delivered easily. There are other agents, including nitric oxide and carbon monoxide which have similar although perhaps not so all-encompassing effects, and comparisons are clearly needed. However, the key molecule can be delivered by other routes. The Pittsburgh group has shown an advantage to experimental cardiac grafts just by putting hydrogen in drinking water (6). Hydrogen sulphide, inhaled or given intraperitoneally as its sodium salt, has similar beneficial effects in endotoxin, oxygen-induced, ventilator-induced, or smoke-induced lung injury. Systemically, it is a free-radical scavenger, upregulates heme-oxygenase-1 gene expression and protects the heart through activation of endothelial K+-ATPase channels (7). This article takes us a step further in reducing lung injury before transplantation. It shows us that modifying how we do EVLP with good lungs has benefits, which can in all probability be translated into what we do with the predamaged lungs we take from donors. However, by illustrating the potential for manipulation during normothermic perfusion, it shows a potential route to improving all organs, www.transplantjournal.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
497
498
www.transplantjournal.com
not just those we can inflate, and so it is a benefit across the transplant spectrum. REFERENCES 1.
2.
Avlonitis VS, Wigfield CH, Kirby JA, et al. The hemodynamic mechanisms of lung injury and systemic inflammatory response following brain death in the transplant donor. Am J Transplant 2005; 5: 684. Aitchison JD, Orr HE, Flecknell PA, et al. Functional assessment of nonYheart-beating donor lungs: prediction of post-transplant function. Eur J Cardiothorac Surg 2001; 20: 187.
Transplantation
3. 4. 5. 6. 7.
& Volume 98, Number 5, September 15, 2014
Steen S, Sjoberg T, Pierre L, et al. Transplantation of lungs from a nonYheart beating donor. Lancet 2001; 375: 825. Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med 2011; 364: 1431. Koike TYJ, Cypel M. Kinetics of lactate metabolism during acellular normothermic ex-vivo lung perfusion. J Heart Lung Transplant 2011; 30: 1312. Noda K, Tanaka Y, Shigemura N, et al. Hydrogen-supplemented drinking water protects cardiac allografts from inflammation-associated deterioration. Transpl Int 2012; 25: 1213. Polhemus DJ, Lefer DJ. Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule in cardiovascular disease. Circ Res 2014; 114: 730.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
AND
COMMENTARY
Hydrogen in Lung ReconditioningVMore Than Just Inflation John Dark
rgan perfusion, with us since the days of Carrel and Lindbergh, is coming into vogue across all of transplantation. As we expand the use of organs from donation after cardio-circulatory death donors, and increasingly appreciate the scope for damage after brain stem death, perfusion of isolated organs is being seen as a solution to some of the problems of both organ number and quality. The lung has lead the way, perhaps not only because it is vulnerability to the sequelae of brain death (1) but also because of its unique suitability to donation after circulatory death. Cellular metabolism of the lung can be maintained by simple inflation, in the absence of a circulation, probably for several hours (2). So ischemia is less an issue than assessment of function. In a life-supporting organ, reliable assessment is crucial. Ex vivo lung perfusion (EVLP) was introduced by Steen et al. (3) specifically for DCD lung assessmentVhis first case involved a Maastricht category ll donor and had excellent function after lung quality could be measured in an objective fashion. Subsequently, it was realized by the group in Lund, then workers in Toronto and finally in centers around the world, that EVLP was also a vehicle to improve, or recondition, lungs initially below the standard needed for primary transplantation (4). The most important step was that of Steen demonstrating, in contrast to previous experience, that endothelial integrity could be maintained. Key ingredients were the absence of white cells, platelets, and complement, a hyperosmolar solution and a perfusion approach which minimized shear stress. So great was the difference from the previous experience of inevitable and progressive pulmonary edema that it has been widely assumed that the circuit did no harm at all to the lung. However, this is a naive viewVas the landmark study by Noda and colleagues from the University of Pittsburgh has demonstrated.
O
The author declares no funding or conflicts of interest. Institute of Cellular Medicine, Newcastle University. Address correspondence to: John Dark, Institute of Cellular Medicine Newcastle University, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom. E-mail: [email protected] Received 6 May 2014. Accepted 8 May 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9805-497 DOI: 10.1097/TP.0000000000000311
Transplantation
& Volume 98, Number 5, September 15, 2014
Using a rat model, they showed that EVLP was associated with a proinflammatory environment. They went on to demonstrate that inhaled hydrogen would ameliorate this state, and the effect translated into better function after transplant of the lungs, and a strikingly low inflammatory cell infiltrate in those transplants. The effects of hydrogen as an antioxidant, anti-inflammatory, and antiapoptotic agent are only just now being realized, and this is the first study of the molecule in EVLP. There were additional effects on the levels of lactate which are more difficult to explain. Glucose metabolism in the lung produces lactate, which is then consumed, in the intact animal, by muscle, kidney, and liver. In the artificial setting of isolated lung perfusion, lactate accumulates just as glucose disappears. Although it generates metabolic acidosis, and high lactate has theoretical disadvantageous effects on some aspects of neutrophil function, studies such as those by Koike at al. in Toronto have shown no bad effect on the lung (5). However, hydrogen is clearly having some effect at mitochondrial level, perhaps through the heme-oxygenase-1 pathway. That this is of potential real benefit, regardless of mechanism, is shown by improved adenosine triphospate levels in the lungs exposed to hydrogen. It is a pity that lactate-to-pyruvate ratios, a simple way of looking at some aspects of lactate production, were not measured. The lung has huge advantages, in that the beneficial agent, hydrogen here, can be delivered easily. There are other agents, including nitric oxide and carbon monoxide which have similar although perhaps not so all-encompassing effects, and comparisons are clearly needed. However, the key molecule can be delivered by other routes. The Pittsburgh group has shown an advantage to experimental cardiac grafts just by putting hydrogen in drinking water (6). Hydrogen sulphide, inhaled or given intraperitoneally as its sodium salt, has similar beneficial effects in endotoxin, oxygen-induced, ventilator-induced, or smoke-induced lung injury. Systemically, it is a free-radical scavenger, upregulates heme-oxygenase-1 gene expression and protects the heart through activation of endothelial K+-ATPase channels (7). This article takes us a step further in reducing lung injury before transplantation. It shows us that modifying how we do EVLP with good lungs has benefits, which can in all probability be translated into what we do with the predamaged lungs we take from donors. However, by illustrating the potential for manipulation during normothermic perfusion, it shows a potential route to improving all organs, www.transplantjournal.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
497
498
www.transplantjournal.com
not just those we can inflate, and so it is a benefit across the transplant spectrum. REFERENCES 1.
2.
Avlonitis VS, Wigfield CH, Kirby JA, et al. The hemodynamic mechanisms of lung injury and systemic inflammatory response following brain death in the transplant donor. Am J Transplant 2005; 5: 684. Aitchison JD, Orr HE, Flecknell PA, et al. Functional assessment of nonYheart-beating donor lungs: prediction of post-transplant function. Eur J Cardiothorac Surg 2001; 20: 187.
Transplantation
3. 4. 5. 6. 7.
& Volume 98, Number 5, September 15, 2014
Steen S, Sjoberg T, Pierre L, et al. Transplantation of lungs from a nonYheart beating donor. Lancet 2001; 375: 825. Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med 2011; 364: 1431. Koike TYJ, Cypel M. Kinetics of lactate metabolism during acellular normothermic ex-vivo lung perfusion. J Heart Lung Transplant 2011; 30: 1312. Noda K, Tanaka Y, Shigemura N, et al. Hydrogen-supplemented drinking water protects cardiac allografts from inflammation-associated deterioration. Transpl Int 2012; 25: 1213. Polhemus DJ, Lefer DJ. Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule in cardiovascular disease. Circ Res 2014; 114: 730.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
