Am J Physiol Lung Cell Mol Physiol 307: L908, 2014; doi:10.1152/ajplung.00282.2014.
Letter to the Editor
Antagonizing reactive oxygen species during ex vivo lung perfusion Mohamed S. A. Mohamed Thoracic Transplantation Department, University Clinic Essen, Essen, Germany Submitted 2 October 2014; accepted in final form 26 October 2014 TO THE EDITOR:
The stop of flow (ischemia) would be interpreted as membrane depolarization, through the inhibition of KATP channels, leading to activation of NADPH oxidase, leading to increased reactive oxygen species (ROS) production (1). The resultant ROS are claimed to be an effective mediator for ischemic preconditioning (IPC), as proved by the observation that the presence of antioxidants during the preconditioning phase can diminish the degree of protection (2). However, another important mediator would be KATP channels, whose activation was found to protect against subsequent ischemic events (3). In short, to follow the recommendations of Chatterjee et al. (1) in the IPC model, the method of choice to protect against increased ROS production would be the use of K⫹ channel agonists. In lung transplantation, the graft is subjected to a period of cold static ischemia followed by reperfusion, in the recipient or during ex vivo lung perfusion (EVLP). After EVLP the lung would be subjected again to a period of no flow (ischemia). Considering this scenario, EVLP might be considered as IPC, with the same recommendation applied. In addition, of the different ischemic reperfusion lung injuries (e.g., pulmonary bypass during surgery), lung transplantation takes the big focus regarding initiation of immune reactions and graft rejection. In this regard, increased ROS production and diminished K⫹ channel activity would be involved in the activation of inflammasomes, which when activated result in activation of caspase 1, which in turn activates pro-IL-1 and IL-18, which are proinflammatory cytokines (e.g., IL-1 was found to induce IL-6) (4, 6). Address for reprint requests and other correspondence: M. S. A. Mohamed, Thoracic Transplantation Dept., Univ. Clinic Essen, Hufeland Straße 55, D-55147 Essen, Germany (e-mail: [email protected]).
L908
In a previous study, the use of 2% hydrogen inhalation during EVLP resulted in improved mitochondrial function and improved ATP production. The improved ATP production would improve the activity of KATP channels. The outcome was significantly diminished cytokine production within the graft (5). Accordingly, the inclusion of antioxidants and K⫹ channel agonists during lung graft preservation and EVLP would be of great value from the aspect of antagonizing the role of ROS in the expression of endothelial cell adhesion molecules, which is important for inflammatory cells migration and graft infiltration (1), as well as from the aspect of antagonizing inflammasomes activation and increased cytokine production. REFERENCES 1. Chatterjee S, Nieman FF, Christie JD, Fisher AB. Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307: L668 –L680, 2014. 2. Forbes RA, Steenbergen C, Murphy E. Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism. Circ Res 88: 802–809, 2001. 3. Hu X, Yang Z, Yang M, Qian J, Cahoon J, Xu J, Sun S, Tang W. Remote ischemic preconditioning mitigates myocardial and neurological dysfunction via KATP channel activation in a rat model of hemorrhagic shock. Shock 42: 228 –233, 2014. 4. Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, Takahashi Y, Masumoto J, Koyama J, Hongo M, Noda T, Nakayama J, Sagara J, Taniguchi S, Ikeda U. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123: 594 –604, 2011. 5. Noda K, Shigemura N, Tanaka Y, Bhama J, D’Cunha J, Kobayashi H, Luketich JD, Bermudez CA. Hydrogen preconditioning during ex vivo lung perfusion improves the quality of lung grafts in rats. Transplantation 98: 499 –506, 2014. 6. Triantafilou K, Triantafilou M. Ion flux in the lung: virus-induced inflammasome activation. Trends Microbiol 22: 580 –588, 2014.
1040-0605/14 Copyright © 2014 the American Physiological Society
http://www.ajplung.org
Am J Physiol Lung Cell Mol Physiol 307: L909, 2014; doi:10.1152/ajplung.00310.2014.
Letter to the Editor
Response to letter by Dr. M. S. A. Mohamed (Antagonizing reactive oxygen species during lung perfusion) Shampa Chatterjee,1 Gary F. Nieman,2 Jason D. Christie,3 and Aron B. Fisher1 1
Institute for Environmental Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Surgery, SUNY Upstate Medical University, Syracuse, New York; and 3Pulmonary Allergy and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
2
Submitted 27 October 2014; accepted in final form 29 October 2014 TO THE EDITOR: We thank Dr. M. S. A. Mohamed for his insightful comments regarding our recent paper on endothelial mechanosignaling and its implications in lung transplant (1). We are glad that, as emphasized by our article, the author agrees that the use of KATP channel agonist(s) would be a good strategy to reduce oxidative damage during storage of lungs. Our suggested use of a KATP agonist (in this case cromakalim) in the (lung) graft preservation solution is based on our signaling studies showing that depolarization resulting from closure of this channel drives reactive oxygen species (ROS) production with ischemia (2, 3, 6). Dr. Mohamed suggests another possibility. He raises the point that ischemia reperfusion (I/R) with lung transplant is akin to ischemic preconditioning, or IPC, which has widely been reported to be protective in several organs. The protection afforded by IPC arises, in part, from activation of KATP channels. Thus, based on the IPC model, use of a KATP agonist would be an obvious choice for reduction of oxidative damage. But although the protective effect of IPC or multiple short episodes (1–3 min) of ischemia followed by reperfusion are known in the central nervous and cardiac systems, there are relatively limited data related to the effects of IPC on lungs. Besides the storage of lungs and the standard EVLP (ex vivo lung perfusion) technique does not mimic an IPC maneuver per se (the ischemic times are considerably longer and range between 1– 6 h and the reperfusion too is for longer periods). However, it is possible, as suggested by the author, that having short periods of ischemia, with a period of perfusion between them for EVLP, may reduce oxidative damage. The IPC effect with lung I/R has often been via systemic preconditioning by other remote organ ischemia (such as hind limb or heart) (4, 5). Thus further study of the role of IPC in lung I/R and on the EVLP maneuver is warranted. As suggested by Dr. Mohamed, antagonizing ROS by addition of antioxidants to the lung preservation solution would (by blocking oxidative damage and the inflammation cascade) be a reasonable protective strategy. Thus the hydrogen gas therapy
Address for reprint requests and other correspondence: S. Chatterjee, Institute for Environmental Medicine, Univ. of Pennsylvania, 3620 Hamilton Walk, 1 John Morgan Bldg., Philadelphia, PA 19104 (e-mail: shampac@mail. med.upenn.edu).
http://www.ajplung.org
with EVLP may hold promise due to its antioxidant effects but this has been incompletely assessed till date. Alternatively, inhibiting the cascade that leads to ROS production with lung I/R rather than scavenging ROS after they are produced may be a better approach. This is partly because protective antioxidant therapy has had a mixed clinical response so far and because theoretically it is difficult for a ROS scavenger to compete with tissue components for reaction with ROS. Of course, this is not to indicate that the addition of antioxidants either alone or in combination with KATP agonist(s) to the lung perfusate or storage solution would have no additional protective effect. Signaling upon transplant represents the amalgamation of several events. Besides I/R, immunological, inflammatory, and attendant innate immune responses also play a role in oxidative damage and the pathogenesis of graft dysfunction. Understanding these pathways and how they intersect can help identify agents that can attenuate the signaling events that drive this pathogenesis. In this direction, our article highlights how our understanding of the events in the pulmonary endothelial “mechanosignaling” cascade can translate into inclusion of agents in the preservation solution of lung grafts. REFERENCES 1. Chatterjee S, Nieman GF, Christie JD, Fisher AB. Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307: L668 –L680, 2014. 2. Chatterjee S, Browning EA, Hong N, DeBolt K, Sorokina EM, Liu W, Birnbaum MJ, Fisher AB. Membrane depolarization is the trigger for PI3K/Akt activation and leads to the generation of ROS. Am J Physiol Heart Circ Physiol 302: H105–H114, 2012. 3. Chatterjee S, Levitan I, Wei Z, Fisher AB. KATP channels are an important component of the shear-sensing mechanism in the pulmonary microvasculature. Microcirculation 13: 633–644, 2006. 4. Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury—a review. J Surg Res 150: 304 –330, 2008. 5. Waldow T, Alexiou K, Witt W, Albrecht S, Wagner F, Knaut M, Matschke K. Protection against acute porcine lung ischemia/reperfusion injury by systemic preconditioning via hind limb ischemia. Transpl Int 18: 198 –205, 2005. 6. Zhang Q, Matsuzaki I, Chatterjee S, Fisher AB. Activation of endothelial NADPH oxidase during normoxic lung ischemia is KATP channel dependent. Am J Physiol Lung Cell Mol Physiol 289: L954 –L961, 2005.
1040-0605/14 Copyright © 2014 the American Physiological Society
L909
Copyright of American Journal of Physiology: Lung Cellular & Molecular Physiology is the property of American Physiological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Letter to the Editor
Antagonizing reactive oxygen species during ex vivo lung perfusion Mohamed S. A. Mohamed Thoracic Transplantation Department, University Clinic Essen, Essen, Germany Submitted 2 October 2014; accepted in final form 26 October 2014 TO THE EDITOR:
The stop of flow (ischemia) would be interpreted as membrane depolarization, through the inhibition of KATP channels, leading to activation of NADPH oxidase, leading to increased reactive oxygen species (ROS) production (1). The resultant ROS are claimed to be an effective mediator for ischemic preconditioning (IPC), as proved by the observation that the presence of antioxidants during the preconditioning phase can diminish the degree of protection (2). However, another important mediator would be KATP channels, whose activation was found to protect against subsequent ischemic events (3). In short, to follow the recommendations of Chatterjee et al. (1) in the IPC model, the method of choice to protect against increased ROS production would be the use of K⫹ channel agonists. In lung transplantation, the graft is subjected to a period of cold static ischemia followed by reperfusion, in the recipient or during ex vivo lung perfusion (EVLP). After EVLP the lung would be subjected again to a period of no flow (ischemia). Considering this scenario, EVLP might be considered as IPC, with the same recommendation applied. In addition, of the different ischemic reperfusion lung injuries (e.g., pulmonary bypass during surgery), lung transplantation takes the big focus regarding initiation of immune reactions and graft rejection. In this regard, increased ROS production and diminished K⫹ channel activity would be involved in the activation of inflammasomes, which when activated result in activation of caspase 1, which in turn activates pro-IL-1 and IL-18, which are proinflammatory cytokines (e.g., IL-1 was found to induce IL-6) (4, 6). Address for reprint requests and other correspondence: M. S. A. Mohamed, Thoracic Transplantation Dept., Univ. Clinic Essen, Hufeland Straße 55, D-55147 Essen, Germany (e-mail: [email protected]).
L908
In a previous study, the use of 2% hydrogen inhalation during EVLP resulted in improved mitochondrial function and improved ATP production. The improved ATP production would improve the activity of KATP channels. The outcome was significantly diminished cytokine production within the graft (5). Accordingly, the inclusion of antioxidants and K⫹ channel agonists during lung graft preservation and EVLP would be of great value from the aspect of antagonizing the role of ROS in the expression of endothelial cell adhesion molecules, which is important for inflammatory cells migration and graft infiltration (1), as well as from the aspect of antagonizing inflammasomes activation and increased cytokine production. REFERENCES 1. Chatterjee S, Nieman FF, Christie JD, Fisher AB. Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307: L668 –L680, 2014. 2. Forbes RA, Steenbergen C, Murphy E. Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism. Circ Res 88: 802–809, 2001. 3. Hu X, Yang Z, Yang M, Qian J, Cahoon J, Xu J, Sun S, Tang W. Remote ischemic preconditioning mitigates myocardial and neurological dysfunction via KATP channel activation in a rat model of hemorrhagic shock. Shock 42: 228 –233, 2014. 4. Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, Takahashi Y, Masumoto J, Koyama J, Hongo M, Noda T, Nakayama J, Sagara J, Taniguchi S, Ikeda U. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123: 594 –604, 2011. 5. Noda K, Shigemura N, Tanaka Y, Bhama J, D’Cunha J, Kobayashi H, Luketich JD, Bermudez CA. Hydrogen preconditioning during ex vivo lung perfusion improves the quality of lung grafts in rats. Transplantation 98: 499 –506, 2014. 6. Triantafilou K, Triantafilou M. Ion flux in the lung: virus-induced inflammasome activation. Trends Microbiol 22: 580 –588, 2014.
1040-0605/14 Copyright © 2014 the American Physiological Society
http://www.ajplung.org
Am J Physiol Lung Cell Mol Physiol 307: L909, 2014; doi:10.1152/ajplung.00310.2014.
Letter to the Editor
Response to letter by Dr. M. S. A. Mohamed (Antagonizing reactive oxygen species during lung perfusion) Shampa Chatterjee,1 Gary F. Nieman,2 Jason D. Christie,3 and Aron B. Fisher1 1
Institute for Environmental Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Surgery, SUNY Upstate Medical University, Syracuse, New York; and 3Pulmonary Allergy and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
2
Submitted 27 October 2014; accepted in final form 29 October 2014 TO THE EDITOR: We thank Dr. M. S. A. Mohamed for his insightful comments regarding our recent paper on endothelial mechanosignaling and its implications in lung transplant (1). We are glad that, as emphasized by our article, the author agrees that the use of KATP channel agonist(s) would be a good strategy to reduce oxidative damage during storage of lungs. Our suggested use of a KATP agonist (in this case cromakalim) in the (lung) graft preservation solution is based on our signaling studies showing that depolarization resulting from closure of this channel drives reactive oxygen species (ROS) production with ischemia (2, 3, 6). Dr. Mohamed suggests another possibility. He raises the point that ischemia reperfusion (I/R) with lung transplant is akin to ischemic preconditioning, or IPC, which has widely been reported to be protective in several organs. The protection afforded by IPC arises, in part, from activation of KATP channels. Thus, based on the IPC model, use of a KATP agonist would be an obvious choice for reduction of oxidative damage. But although the protective effect of IPC or multiple short episodes (1–3 min) of ischemia followed by reperfusion are known in the central nervous and cardiac systems, there are relatively limited data related to the effects of IPC on lungs. Besides the storage of lungs and the standard EVLP (ex vivo lung perfusion) technique does not mimic an IPC maneuver per se (the ischemic times are considerably longer and range between 1– 6 h and the reperfusion too is for longer periods). However, it is possible, as suggested by the author, that having short periods of ischemia, with a period of perfusion between them for EVLP, may reduce oxidative damage. The IPC effect with lung I/R has often been via systemic preconditioning by other remote organ ischemia (such as hind limb or heart) (4, 5). Thus further study of the role of IPC in lung I/R and on the EVLP maneuver is warranted. As suggested by Dr. Mohamed, antagonizing ROS by addition of antioxidants to the lung preservation solution would (by blocking oxidative damage and the inflammation cascade) be a reasonable protective strategy. Thus the hydrogen gas therapy
Address for reprint requests and other correspondence: S. Chatterjee, Institute for Environmental Medicine, Univ. of Pennsylvania, 3620 Hamilton Walk, 1 John Morgan Bldg., Philadelphia, PA 19104 (e-mail: shampac@mail. med.upenn.edu).
http://www.ajplung.org
with EVLP may hold promise due to its antioxidant effects but this has been incompletely assessed till date. Alternatively, inhibiting the cascade that leads to ROS production with lung I/R rather than scavenging ROS after they are produced may be a better approach. This is partly because protective antioxidant therapy has had a mixed clinical response so far and because theoretically it is difficult for a ROS scavenger to compete with tissue components for reaction with ROS. Of course, this is not to indicate that the addition of antioxidants either alone or in combination with KATP agonist(s) to the lung perfusate or storage solution would have no additional protective effect. Signaling upon transplant represents the amalgamation of several events. Besides I/R, immunological, inflammatory, and attendant innate immune responses also play a role in oxidative damage and the pathogenesis of graft dysfunction. Understanding these pathways and how they intersect can help identify agents that can attenuate the signaling events that drive this pathogenesis. In this direction, our article highlights how our understanding of the events in the pulmonary endothelial “mechanosignaling” cascade can translate into inclusion of agents in the preservation solution of lung grafts. REFERENCES 1. Chatterjee S, Nieman GF, Christie JD, Fisher AB. Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307: L668 –L680, 2014. 2. Chatterjee S, Browning EA, Hong N, DeBolt K, Sorokina EM, Liu W, Birnbaum MJ, Fisher AB. Membrane depolarization is the trigger for PI3K/Akt activation and leads to the generation of ROS. Am J Physiol Heart Circ Physiol 302: H105–H114, 2012. 3. Chatterjee S, Levitan I, Wei Z, Fisher AB. KATP channels are an important component of the shear-sensing mechanism in the pulmonary microvasculature. Microcirculation 13: 633–644, 2006. 4. Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury—a review. J Surg Res 150: 304 –330, 2008. 5. Waldow T, Alexiou K, Witt W, Albrecht S, Wagner F, Knaut M, Matschke K. Protection against acute porcine lung ischemia/reperfusion injury by systemic preconditioning via hind limb ischemia. Transpl Int 18: 198 –205, 2005. 6. Zhang Q, Matsuzaki I, Chatterjee S, Fisher AB. Activation of endothelial NADPH oxidase during normoxic lung ischemia is KATP channel dependent. Am J Physiol Lung Cell Mol Physiol 289: L954 –L961, 2005.
1040-0605/14 Copyright © 2014 the American Physiological Society
L909
Copyright of American Journal of Physiology: Lung Cellular & Molecular Physiology is the property of American Physiological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
