The HMGB1-RAGE Inflammatory Pathway: Implications for Brain Injury-Induced Pulmonary Dysfunction.
CONCLUSIONS
Deceased patients who have suffered severe traumatic brain injury (TBI) are the largest source of organs for lung transplantation. However, due to severely compromised pulmonary lung function, only one-third of these patients are eligible organ donors, with far fewer capable of donating lungs (∼ 20%). As a result of this organ scarcity, understanding and controlling the pulmonary pathophysiology of potential donors are key to improving the health and long-term success of transplanted lungs.


BACKGROUND
Although the exact mechanism by which TBI produces pulmonary pathophysiology remains unclear, it may be related to the release of damage-associated molecular patterns (DAMPs) from the injured tissue. These heterogeneous, endogenous host molecules can be rapidly released from damaged or dying cells and mediate sterile inflammation following trauma. In this review, we highlight the interaction of the DAMP, high-mobility group box protein 1 (HMGB1) with the receptor for advanced glycation end-products (RAGE), and toll-like receptor 4 (TLR4).


RESULTS
Recently published studies are reviewed, implicating the release of HMGB1 as producing marked changes in pulmonary inflammation and physiology following trauma, followed by an overview of the experimental evidence demonstrating the benefits of blocking the HMGB1-RAGE axis.


CONCLUSIONS
Targeting the HMGB1 signaling axis may increase the number of lungs available for transplantation and improve long-term benefits for organ recipient patient outcomes.
1 Center for Immunobiology, Indiana University School of Medicine , Indianapolis, Indiana.|2 Department of Surgery, Indiana University School of Medicine , Indianapolis, Indiana.
Daniel J
DJ
Weber
3 Department of Anatomy and Cell Biology, Indiana University School of Medicine , Indianapolis, Indiana.
Yohance M
YM
Allette
1 Center for Immunobiology, Indiana University School of Medicine , Indianapolis, Indiana.|4 Department of Medicine, Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, Indiana.
David S
DS
Wilkes
1 Center for Immunobiology, Indiana University School of Medicine , Indianapolis, Indiana.|5 Department of Anesthesia, Indiana University School of Medicine , Indianapolis, Indiana.
Fletcher A
FA
White
D001930:Brain Injuries / Q000276:immunology*; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism; D055370:Lung Injury / Q000276:immunology*; D016040:Lung Transplantation; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D000067759:Receptor for Advanced Glycation End Products; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4