The HMGB1-RAGE axis mediates traumaticbrain injury - Induced pulmonary dysfunction in lung transplantation

Daniel J. Weber, Adam S.A. Gracon, Matthew S. Ripsch, Amanda J. Fisher, Bo M. Cheon, Pankita H. Pandya, Ragini Vittal, Maegan L. Capitano, Youngsook Kim, Yohance M. Allette, Amanda A. Riley, Brian P. McCarthy, Paul R. Territo, Gary D. Hutchins, Hal E. Broxmeyer, George E. Sandusky, Fletcher A. White, David S. Wilkes

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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 (ameasure 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.

Original languageEnglish (US)
Article number252ra124
JournalScience Translational Medicine
Issue number252
StatePublished - Sep 3 2014

All Science Journal Classification (ASJC) codes

  • General Medicine

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