Early release of high mobility group box nuclear protein 1 after severe trauma in humans: role of injury severity and tissue hypoperfusion.
BACKGROUND
High mobility group box nuclear protein 1 (HMGB1) is a DNA nuclear binding protein that has recently been shown to be an early trigger of sterile inflammation in animal models of trauma-hemorrhage via the activation of the Toll-like-receptor 4 (TLR4) and the receptor for the advanced glycation endproducts (RAGE). However, whether HMGB1 is released early after trauma hemorrhage in humans and is associated with the development of an inflammatory response and coagulopathy is not known and therefore constitutes the aim of the present study.


METHODS
One hundred sixty eight patients were studied as part of a prospective cohort study of severe trauma patients admitted to a single Level 1 Trauma center. Blood was drawn within 10 minutes of arrival to the emergency room before the administration of any fluid resuscitation. HMGB1, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, von Willebrand Factor (vWF), angiopoietin-2 (Ang-2), Prothrombin time (PT), prothrombin fragments 1+2 (PF1+2), soluble thrombomodulin (sTM), protein C (PC), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and D-Dimers were measured using standard techniques. Base deficit was used as a measure of tissue hypoperfusion. Measurements were compared to outcome measures obtained from the electronic medical record and trauma registry.


RESULTS
Plasma levels of HMGB1 were increased within 30 minutes after severe trauma in humans and correlated with the severity of injury, tissue hypoperfusion, early posttraumatic coagulopathy and hyperfibrinolysis as well with a systemic inflammatory response and activation of complement. Non-survivors had significantly higher plasma levels of HMGB1 than survivors. Finally, patients who later developed organ injury, (acute lung injury and acute renal failure) had also significantly higher plasma levels of HMGB1 early after trauma.


CONCLUSIONS
The results of this study demonstrate for the first time that HMGB1 is released into the bloodstream early after severe trauma in humans. The release of HMGB1 requires severe injury and tissue hypoperfusion, and is associated with posttraumatic coagulation abnormalities, activation of complement and severe systemic inflammatory response.
Cohen
Mitchell J
MJ
The Department of Surgery, San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA. mcohen@sfghsurg.ucsf.edu
Brohi
Karim
K
Calfee
Carolyn S
CS
Rahn
Pamela
P
Chesebro
Brian B
BB
Christiaans
Sarah C
SC
Carles
Michel
M
Howard
Marybeth
M
Pittet
Jean-François
JF
D000328:Adult; D001794:Blood Pressure; D001798:Blood Proteins / Q000032:analysis; D015331:Cohort Studies; D006259:Craniocerebral Trauma / Q000097:blood / Q000150:complications; D005260:Female; D024243:HMGB1 Protein / Q000097:blood* / Q000378:metabolism; D006339:Heart Rate; D006801:Humans; D007249:Inflammation / Q000097:blood; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011517:Prothrombin Time; D012121:Respiration, Artificial; D012151:Resuscitation / Q000379:methods; D017741:Survivors; D014193:Trauma Centers; D014947:Wounds and Injuries / Q000097:blood* / Q000150:complications* / Q000401:mortality / Q000628:therapy; D014950:Wounds, Penetrating / Q000097:blood / Q000150:complications
D001798:Blood Proteins; D024243:HMGB1 Protein