The HMGB1-RAGE axis mediates traumatic brain injury–induced pulmonary dysfunction in lung transplantation

Abstract

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 (wildtype) or deficient (RAGE−/−) C57BL/6 mice were subjected to TBI through controlled cortical impact and studied for cardio-pulmonary injury. Compared to control animals, TBI induced systemic hypoxia, acute lung injury, pulmonary neutrophilia and decreased compliance, all of which were attenuated in RAGE −/− mice. Neutralizing systemic HMGB1, induced by TBI, reversed hypoxia and improved lung compliance. Compared to wildtype 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 pre-transplantation and predicted impaired oxygenation post-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 prior to transplant may improve recipient outcomes following lung transplantation.

RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis

“…4). RAGE deficiency leads to increased IL-10 production by T cells in vitro (37) as well as to increased IL-10 levels in murine models of hemorrhagic shock (38) and traumatic brain injury-induced pulmonary dysfunction (39) and in mice fed a high fat diet (40). Therefore, our finding of RAGE-dependent suppression of IL-10 production is consistent with the findings of others.…”

Circulating mitochondria in deceased organ donors are associated with immune activation and early allograft dysfunction

“…This is likely reflective of the diverse heterogeneity in age, health status, cause of death, and other donor factors among our study cohort. Although traumatic injury has been shown to promote the release of DAMPs and to effect organ quality in previous studies (25,26,55), we found no associations between traumatic brain injury and levels of mtDNA or EAD in our cohort. However, we did identify a significant correlation between KDPI and the PMN-activating qualities of donor plasma, indicating that a donor's health status can affect their inflammatory state.…”

Erythropoietin-Derived Peptide Protects Against Acute Lung Injury After Rat Traumatic Brain Injury

“…Also, reducing the expression of iNOS can protect mice from ALI [32], demonstrating that these inflammatory mediators are essential to TBI-induced ALI. Conversely, the anti-inflammatory cytokine IL-10 is reported to protect mice from the inflammation process in TBI-induced ALI [33]. In the current study, we discovered that pHBSP ameliorated TBI-induced decrease of PaO 2 , and pHBSP significantly decreased TBI-induced up-regulation of TNF-α, IL-6, IL-1β and iNOS mRNA expression in the lung, while up-regulated the mRNA expression level of IL-10 in the lung.…”