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) (Impact Factor: 4.48). 11/2009; 13(6):R174. DOI: 10.1186/cc8152
Source: PubMed


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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Available from: Karim Brohi, Nov 05, 2015
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    • "15), being 30 times greater than those in controls 1 h after injury, and peaking 2–6 h post injury [39]. Moreover, high levels of HMGB1 have been shown to be associated with injury severity score and survival [68]. The release of HMGB1 into the circulation following trauma has since been linked to the subsequent inflammatory response. "
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    ABSTRACT: A well described consequence of traumatic injury is immune dysregulation, where an initial increase in immune activity is followed by a period of immune depression, the latter leaving hospitalised trauma patients at an increased risk of nosocomial infections. Here, we discuss the emerging role of the neutrophil, the most abundant leucocyte in human circulation and the first line of defence against microbial challenge, in the initiation and propagation of the inflammatory response to trauma. We review the findings of the most recent studies to have investigated the impact of trauma on neutrophil function and discuss how alterations in neutrophil biology are being investigated as potential biomarkers by which to predict the outcome of hospitalised trauma patients. Furthermore, with trauma-induced changes in neutrophil biology linked to the development of such post-traumatic complications as multiple organ failure and acute respiratory distress syndrome, we highlight an area of research within the field of trauma immunology that is gaining considerable interest: the manipulation of neutrophil function as a means by which to potentially improve patient outcome.
    Injury 07/2014; 45(12). DOI:10.1016/j.injury.2014.06.021 · 2.14 Impact Factor
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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: Background: 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. Methods: All patients with severe blunt chest trauma (abbreviated injury score ≥3) who were admitted to traumatic surgery department and ultimately survived to follow-up at 6 mo were eligible for the study. HMGB1 was sampled every other day from day 1-day 7 after admission, and plasma concentrations of HMGB1 were measured by a quantitative enzyme-linked immunosorbent assay test. Multivariate regression analysis was used to define the independent contribution of possible risk factors selected by univariate analysis. Results: PTSD was identified in 43 patients including acute PTSD (n = 21), chronic PTSD (n = 18), and delayed-onset PTSD (n = 4) after 6-mo follow-up, in whom significant higher plasma levels of HMGB1 on days three, five, and seven after blunt chest trauma were noted compared with those seen in patients without PTSD (n = 10). Multivariate logistic analysis showed that transfusion, injury severity score, and HMGB1 levels at day 7 were the valuable risk factors for PTSD. Conclusions: In blunt chest trauma, plasma HMGB1 levels were significantly higher in patients with PTSD compared with patients with non-PTSD. Our data indicate that patients with high plasma levels of HMGB1 may be more prone to develop PTSD including acute and chronic PTSD.
    Journal of Surgical Research 06/2014; 193(1). DOI:10.1016/j.jss.2014.06.020 · 1.94 Impact Factor
    • "Tissue injury accompanying massive trauma results in immediate increases in circulating levels of damage-associated molecular patterns (DAMPs) like high-mobility group box1 (HMGB1) and nucleic acids including histone-complexed DNA (nucleosomes),[123456] and endogenous molecules that signal tissue and cell damage.[67] Trauma remains a major cause of death and disability worldwide[8] and since hemorrhage accounts for most early trauma deaths,[9] much attention has been given to the early trauma-induced coagulopathy (TIC).[10] "
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    ABSTRACT: Tissue injury increases blood levels of extracellular histones and nucleic acids, and these may influence hemostasis, promote inflammation and damage the endothelium. Trauma-induced coagulopathy (TIC) may result from an endogenous response to the injury that involves the neurohumoral, inflammatory and hemostatic systems. To study the contribution of extracellular nucleic constituents to TIC, inflammation and endothelial damage. Prospective observational study. We investigated histone-complexed DNA fragments (hcDNA) along with biomarkers of coagulopathy, inflammation and endothelial damage in plasma from 80 trauma patients admitted directly to the Trauma Centre from the scene of the accident. Blood was sampled a median of 68 min (IQR 48-88) post injury. Trauma patients with hcDNA levels >median or ≤median were compared. Trauma patients with high plasma hcDNA had higher Injury Severity Score (ISS) and level of sympathoadrenal activation (higher adrenaline and noradrenaline) and a higher proportion of prolonged activated partial thromboplastin time (APTT) and higher D-dimer, tissue-type plasminogen activator (tPA), Annexin V and soluble CD40 ligand (sCD40L) concurrent with lower plasminogen activator inhibitor (PAI)-1) and prothrombin fragment (PF) 1 + 2 (all P < 0.05), all indicative of impaired thrombin generation, hyperfibrinolysis and platelet activation. Furthermore, patients with high hcDNA had enhanced inflammation and endothelial damage evidenced by higher plasma levels of terminal complement complex (sC5b-9), IL-6, syndecan-1, thrombomodulin and tissue factor pathway inhibitor (all P < 0.05). Excessive release of extracellular histones and nucleic acids seems to contribute to the hypocoagulability, inflammation and endothelial damage observed early after trauma.
    Journal of Emergencies Trauma and Shock 07/2013; 6(3):171-5. DOI:10.4103/0974-2700.115327
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