Bo M. Cheon

TL;DR: In this article, the authors investigated the role of high-mobility group box-1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE) in lung transplant.

TL;DR: Data suggest that the HMGB1-RAGE axis plays a role in the mechanism by which TBI induces lung dysfunction and that targeting this pathway before transplant may improve recipient outcomes after lung transplantation.

Abstract: Traumatic brain injury induces acute lung injury that negatively impacts the physiology of the donor lung before and after lung transplantation. Sounding the Alarm for RAGE Only 20% of lungs are transplantable because traumatic brain injury, a major cause of death in organ doors, may induce acute lung injury. High-mobility group box-1 (HMGB1) release from the injured brain likely contributes to acute lung injury in donors by preferentially interacting with receptor for advanced glycation end products (RAGE) in the lung. Blocking the HMGB1-RAGE axis improves lung function in murine donors with traumatic brain injury and after transplant. In translational studies, lungs sourced from donors with high HMGB1 levels had worse pulmonary function after transplant. Targeting the HMGB1-RAGE axis may increase the number of lungs available for transplantation and improve patient outcomes. Traumatic brain injury (TBI) results in systemic inflammatory responses that affect the lung. This is especially critical in the setting of lung transplantation, where more than half of donor allografts are obtained postmortem from individuals with TBI. The mechanism by which TBI causes pulmonary dysfunction remains unclear but may involve the interaction of high-mobility group box-1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). To investigate the role of HMGB1 and RAGE in TBI-induced lung dysfunction, RAGE-sufficient (wild-type) or RAGE-deficient (RAGE−/−) C57BL/6 mice were subjected to TBI through controlled cortical impact and studied for cardiopulmonary injury. Compared to control animals, TBI induced systemic hypoxia, acute lung injury, pulmonary neutrophilia, and decreased compliance (a measure of the lungs’ ability to expand), all of which were attenuated in RAGE−/− mice. Neutralizing systemic HMGB1 induced by TBI reversed hypoxia and improved lung compliance. Compared to wild-type donors, lungs from RAGE−/− TBI donors did not develop acute lung injury after transplantation. In a study of clinical transplantation, elevated systemic HMGB1 in donors correlated with impaired systemic oxygenation of the donor lung before transplantation and predicted impaired oxygenation after transplantation. These data suggest that the HMGB1-RAGE axis plays a role in the mechanism by which TBI induces lung dysfunction and that targeting this pathway before transplant may improve recipient outcomes after lung transplantation.