Invited Commentary

Abstract

Approximately 40,200 lung transplants have been performed worldwide since 1985, and more than 3,500 lung transplants are performed annually [1Christie J.D. Edwards L.B. Kucheryavaya A.Y. et al.The registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report—2012.Int Soc Heart Lung Transpl. 2012; 31: 1073-1086Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar]. Despite the success of lung transplantation, 20% to 35% of patients experience ischemia-reperfusion injury after lung transplantation [2Ailawadi G. Lau C.L. Smith P.W. et al.Does reperfusion injury still cause significant mortality after lung transplantation?.J Thorac Cardiovasc Surg. 2009; 137: 688-694Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar]. This process results in pulmonary edema and intraalveolar and systemic cytokine release, leading to acute lung injury. Ischemia-reperfusion injury is seen in 30% of early lung transplant deaths in the current surgical era, is often associated with prolonged mechanical ventilation and increased length of hospital stay, and is a known risk factor for the long-term development of bronchiolitis obliterans [3den Hengst W.A. Gielis J.F. Lin J.Y. Van Schil P.E. De Windt L.J. Moens A.L. Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process.Am J Physiol Heart Circ Physiol. 2010; 299: H1283-H1299Crossref PubMed Scopus (250) Google Scholar]. Although factors such as high mechanical stress ventilation and rapid reperfusion have been associated with ischemia-reperfusion injury, little is known about the biology of this phenomenon.At the molecular level, endothelial permeability leading to reperfusion edema is regulated by protein–protein interactions between adjacent cells, called “tight junctions” and “adherens junctions.” At adherens junctions, adhesion is promoted by cadherins (VE-cadherin and N-cadherin), molecules that project out from the endothelial cell membrane. Cadherin binding to fibrin stimulates the opening of adherens junctions, resulting in leakiness of the alveolar-endothelial barrier, causing pulmonary edema and alveolar inflammation. It makes sense that small molecules that inhibit the binding of VE-cadherin and fibrin may attenuate reperfusion injury. In the accompanying article, Tian and colleagues [4Tian Z. Dong B. Blackwell J.W. Stewart P.W. Egan T.M. Effect of a vascular endothelial cadherin antagonist in a rat lung transplant model.Ann Thorac Surg. 2013; 95: 1028-1034Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar] show that treatment of donor and recipient rat lungs with the “B knob” fragment of fibrin (Bβ15-42), a competitive inhibitor of fibrin binding to VE-cadherin, is associated with better oxygenation, enhanced compliance, and lower wet lung weight after transplantation. Similar findings have been reported for use of this drug in the treatment of acute lung injury and in the treatment of ischemia-reperfusion injury in the heart and kidney.In situ lung transplantation in a rat is no easy feat, and the authors should be commended for working with this difficult model system. However, is Bβ15-42 the “magic bullet” to end ischemia-reperfusion? Probably not, for two reasons: First, bronchoalveolar lavage fluid from treated lungs had much higher protein concentrations (protein being a surrogate marker of an exudative process) than the controls lungs. Second, treatment with Bβ15-42 had no significant effect on bronchoalveolar lavage cytokine levels.Nonetheless, this work represents fascinating translational research on one of the Achilles' heels of lung transplantation. It will be interesting to see how new drugs and small molecules that target endothelial junctions, alone or in combination, will fare in animal models of lung transplantation in the future. Approximately 40,200 lung transplants have been performed worldwide since 1985, and more than 3,500 lung transplants are performed annually [1Christie J.D. Edwards L.B. Kucheryavaya A.Y. et al.The registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report—2012.Int Soc Heart Lung Transpl. 2012; 31: 1073-1086Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar]. Despite the success of lung transplantation, 20% to 35% of patients experience ischemia-reperfusion injury after lung transplantation [2Ailawadi G. Lau C.L. Smith P.W. et al.Does reperfusion injury still cause significant mortality after lung transplantation?.J Thorac Cardiovasc Surg. 2009; 137: 688-694Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar]. This process results in pulmonary edema and intraalveolar and systemic cytokine release, leading to acute lung injury. Ischemia-reperfusion injury is seen in 30% of early lung transplant deaths in the current surgical era, is often associated with prolonged mechanical ventilation and increased length of hospital stay, and is a known risk factor for the long-term development of bronchiolitis obliterans [3den Hengst W.A. Gielis J.F. Lin J.Y. Van Schil P.E. De Windt L.J. Moens A.L. Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process.Am J Physiol Heart Circ Physiol. 2010; 299: H1283-H1299Crossref PubMed Scopus (250) Google Scholar]. Although factors such as high mechanical stress ventilation and rapid reperfusion have been associated with ischemia-reperfusion injury, little is known about the biology of this phenomenon. At the molecular level, endothelial permeability leading to reperfusion edema is regulated by protein–protein interactions between adjacent cells, called “tight junctions” and “adherens junctions.” At adherens junctions, adhesion is promoted by cadherins (VE-cadherin and N-cadherin), molecules that project out from the endothelial cell membrane. Cadherin binding to fibrin stimulates the opening of adherens junctions, resulting in leakiness of the alveolar-endothelial barrier, causing pulmonary edema and alveolar inflammation. It makes sense that small molecules that inhibit the binding of VE-cadherin and fibrin may attenuate reperfusion injury. In the accompanying article, Tian and colleagues [4Tian Z. Dong B. Blackwell J.W. Stewart P.W. Egan T.M. Effect of a vascular endothelial cadherin antagonist in a rat lung transplant model.Ann Thorac Surg. 2013; 95: 1028-1034Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar] show that treatment of donor and recipient rat lungs with the “B knob” fragment of fibrin (Bβ15-42), a competitive inhibitor of fibrin binding to VE-cadherin, is associated with better oxygenation, enhanced compliance, and lower wet lung weight after transplantation. Similar findings have been reported for use of this drug in the treatment of acute lung injury and in the treatment of ischemia-reperfusion injury in the heart and kidney. In situ lung transplantation in a rat is no easy feat, and the authors should be commended for working with this difficult model system. However, is Bβ15-42 the “magic bullet” to end ischemia-reperfusion? Probably not, for two reasons: First, bronchoalveolar lavage fluid from treated lungs had much higher protein concentrations (protein being a surrogate marker of an exudative process) than the controls lungs. Second, treatment with Bβ15-42 had no significant effect on bronchoalveolar lavage cytokine levels. Nonetheless, this work represents fascinating translational research on one of the Achilles' heels of lung transplantation. It will be interesting to see how new drugs and small molecules that target endothelial junctions, alone or in combination, will fare in animal models of lung transplantation in the future. Effect of a Vascular Endothelial Cadherin Antagonist in a Rat Lung Transplant ModelThe Annals of Thoracic SurgeryVol. 95Issue 3PreviewAdherens junctions are critically important in control of endothelial cell permeability. Bβ15-42 is a peptide product of fibrin degradation that binds to vascular endothelial cadherin, the major component of endothelial adherens junctions. We tested the hypothesis that Bβ15-42 improves lung function in our rat lung transplant model. Full-Text PDF