Early release of high mobility group box nuclear protein 1 after severe trauma in humans: Role of injury severity and tissue hypoperfusion

The Department of Surgery, San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA.
Critical care (London, England) 11/2009; 13(6):R174. DOI: 10.1186/cc8152
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    • "Blunt chest trauma induces systemic inflammatory response, and is often associated with poor outcome in the late phase of the trauma, which can lead to PTSD. HMGB1 has been demonstrated to play a central role in the initiation and propagation of the inflammatory response with traumatic injury [44] [45]. Moreover, it has been demonstrated that HMGB1 is involved in the ischemiaereperfusion injury of organs [46e48]. "
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    ABSTRACT: High-mobility group box 1 (HMGB1), a key late mediator of systemic inflammation, is a potentially useful biomarker for predicting outcome in patients with severe blunt chest trauma. The purpose of this study was to define the relationship between plasma levels of HMGB1 and posttraumatic stress disorder (PTSD) in patients with severe blunt chest trauma.
    Journal of Surgical Research 06/2014; 193(1). DOI:10.1016/j.jss.2014.06.020 · 2.12 Impact Factor
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    • "The concentration of HMGB1 correlates with the severity of injury and the systemic inflammatory response. Moreover, patients who develop organ dysfunction and nonsurvivors of severe trauma show higher levels of HMGB1 [21]. In a conflicting report, no correlation between increased HMGB1 levels after trauma and injury severity or parameters of patient outcome was found, which might be due to a rather small sample size in the latter study [49]. "
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    ABSTRACT: Sterile injury can cause a systemic inflammatory response syndrome (SIRS) that resembles the host response during sepsis. The inflammatory response following trauma comprises various systems of the human body which are cross-linked with each other within a highly complex network of inflammation. Endogenous danger signals (danger-associated molecular patterns; DAMPs; alarmins) as well as exogenous pathogen-associated molecular patterns (PAMPs) play a crucial role in the initiation of the immune response. With popularization of the "danger theory," numerous DAMPs and PAMPs and their corresponding pathogen-recognition receptors have been identified. In this paper, we highlight the role of the DAMPs high-mobility group box protein 1 (HMGB1), interleukin-1α (IL-1α), and interleukin-33 (IL-33) as unique dual-function mediators as well as mitochondrial danger signals released upon cellular trauma and necrosis.
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