The Next Frontier in Lung Transplantation: Protecting the Endothelium and Repairing Organs for Transplant Utilizing MG53

Abstract

Lung transplantation is plagued by limited access to suitable donor organs. While organs traditionally come from brain dead donors (BDD), these organs from a standard donor do not currently meet the demand of those on the wait list. 1 In recent years, extended criteria donors (ECD) (i.e., donors that were traditionally thought to be of poorer quality) have been utilized with increasing rates and success. 2 However, limitations still exist on the immediate function and long-term implications of their use. 3 ECD, due to their baseline quality, often suffer a disproportionate amount of warm ischemia during the agonal phase of the organ recovery process. Upon their implantation, the reperfusion injury afflicting these allografts triggers a litany of harmful processes (necroptosis, pyroptosis, etc.) that are the cause of immediate poor allograft function and possibly lead to long-term consequences. This process is known as ischemia reperfusion injury (IRI), and all transplanted organs suffer a degree of this injury. At the cellular level, IRI leads to degradation of the pulmonary vascular endothelium, which allows for an influx of immune cells into the alveoli leading to further damage and pulmonary edema. 4 Clinically, the consequence of this inflammatory cascade results in primary graft dysfunction (PGD) within the first 72 h post-transplant, which has deleterious consequences in the immediate post-operative period 5,6 and can lead to long term rejection. [5][6][7] PGD, like any form of acute lung injury (ALI) directly results in endothelial alteration. 8 At the site of gas exchange, the alveolo-endothelial membrane consists of a thin layer of pulmonary vascular endothelial cells and alveolar epithelial cells with their basement membranes fused together. 9 In addition to facilitating the exchange of oxygen, small amounts of fluid also cross this barrier, which is subsequently drained by lymphatics. 10 Upon damage of the pulmonary endothelium (i.e. by IRI), the basement membrane is exposed thus initiating a phenotypic shift from an anti-thrombotic/anti-inflammatory state to a dysfunctional disposition resulting in un-inhibited inflam-This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.