Hmgb1 Is Markedly Elevated Within 6 Hours of Mechanical Trauma in Humans

Peltz, Erik D.; Moore, Ernest E.; Eckels, Phillip; Damle, Sagar S.; Tsuruta, Yuko; Johnson, Jeffrey L.; Sauaia, Angela; Silliman, Christopher C.; Banerjee, Anirban; Abraham, Edward

doi:10.1097/shk.0b013e3181997173

Cited by 172 publications

(161 citation statements)

References 28 publications

(45 reference statements)

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“…Previous studies have reported the release of HMGB1 by ECs following RAGE ligation; however, whether or not HMGB1 is released as a result of cellular activation or necrosis of endothelium has not been described (13,36). Our findings are consistent with previous reports demonstrating elevated HMGB1 levels in patients receiving PRBC transfusions (21). Posttransfusion levels of HMGB1 were higher than what has been reported in transfusates, suggesting that HMGB1 is secreted or released as part of the response to RBC transfusion (21).…”

Section: L259supporting

confidence: 61%

The receptor for advanced glycation end products mediates lung endothelial activation by RBCs

Mangalmurti

Friedman

Wang

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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The receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor implicated in multiple disease states. Although RAGE is expressed on systemic vascular endothelium, the expression and function of RAGE on lung endothelium has not been studied. Utilizing in vitro (human) and in vivo (mouse) models, we established the presence of RAGE on lung endothelium. Because RAGE ligands can induce the expression of RAGE and stored red blood cells express the RAGE ligand N ε -carboxymethyl lysine, we investigated whether red blood cell (RBC) transfusion would augment RAGE expression on endothelium utilizing a syngeneic model of RBC transfusion. RBC transfusion not only increased lung endothelial RAGE expression but enhanced lung inflammation and endothelial activation, since lung high mobility group box 1 and vascular cell adhesion molecule 1 expression was elevated following transfusion. These effects were mediated by RAGE, since endothelial activation was absent in RBCtransfused RAGE knockout mice. Thus, RAGE is inducibly expressed on lung endothelium, and one functional consequence of RBC transfusion is increased RAGE expression and endothelial activation. receptor for advanced glycation end products; red blood cell transfusion; endothelial cell; lung inflammation; red blood cells THE RECEPTOR FOR ADVANCED glycation end products (RAGE) is widely expressed on systemic endothelium and functions as a pattern recognition receptor for multiple ligands, including advanced glycation end products (AGEs), high mobility group box 1 (HMGB1), calgranulins (s100A12 and s100B), amyloid ␤-proteins, Mac-1, phosphotidylserine, and lipopolysaccharide (10,24,26,35). AGEs, a heterogenous group of adducts formed during pathological states, hyperglycemia, and periods of increased oxidative stress, lead to increased generation of reactive oxygen species (ROS) and inflammatory cytokines following ligation of RAGE expressed on vascular endothelium (25,31,32). We have previously shown that stored red blood cells (RBCs) that express the RAGE ligand N ε -carboxymethyl lysine (N ε -CML) trigger lung endothelial ROS generation that was attenuated by soluble receptor for advanced glycation end products (sRAGE), the extracellular ligandbinding domain of the receptor that acts as a decoy by binding RAGE ligands (19). This finding supports the hypothesis that RAGE ligands on the surface of stored RBCs promote activation of lung endothelium, thus contributing to the pathogenesis of lung injury in susceptible transfusion recipients.Because RAGE is abundantly expressed on alveolar epithelium, particularly type I epithelial cells, and is utilized as a specific marker of alveolar epithelial injury, the existence of RAGE on pulmonary endothelium has come into question (9,28,30). Indeed, prior studies failed to detect RAGE in lung endothelium (9, 28). However, the complexities of RAGE biology render it a difficult molecule to study, since RAGE is known to exist in several different isoforms, subject to cleavage by proteases, ra...

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Section: L259supporting

confidence: 61%

The receptor for advanced glycation end products mediates lung endothelial activation by RBCs

Mangalmurti

Friedman

Wang

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…HMGB1 has been reported as a major DAMP released during trauma 34 and presents at a high concentration in bone marrow. 35 To address whether HMGB1 mediates tissue damagesuppression of Mϕ necroptosis in response to LPS, we prepared HMGB1-deficient BCM from femurs and tibias harvested from inducible HMGB1-knockout mice 36 ( Figure 3a), and used the HMGB1-deficient BCM to treat BMDM.…”

Section: Resultsmentioning

confidence: 99%

Tissue damage negatively regulates LPS-induced macrophage necroptosis

Scott

Fan

et al. 2016

Cell Death Differ

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Infection is a common clinical complication following tissue damage resulting from surgery and severe trauma. Studies have suggested that cell pre-activation by antecedent trauma/tissue damage profoundly impacts the response of innate immune cells to a secondary infectious stimulus. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that control cell release of inflammatory mediators from important innate immune executive cells such as macrophages (Mϕ), which critically regulate the progress of inflammation. In this study, we investigated the mechanism and role of trauma/tissue damage in the regulation of LPS-induced Mϕ necroptosis using a mouse model simulating long-bone fracture. We demonstrate that LPS acting through Toll-like receptor (TLR) 4 promotes Mϕ necroptosis. However, necroptosis is ameliorated by high-mobility group box 1 (HMGB1) release from damaged tissue. We show that HMGB1 acting through cell surface receptor for advanced glycation end products (RAGE) upregulates caveolin-1 expression, which in turn induces caveolae-mediated TLR4 internalization and desensitization to decrease Mϕ necroptosis. We further show that RAGE-MyD88 activation of Cdc42 and subsequent activation of transcription factor Sp1 serves as a mechanism underlying caveolin-1 transcriptional upregulation. These results reveal a previous unidentified protective role of damage-associated molecular pattern (DAMP) molecules in restricting inflammation in response to exogenous pathogen-associated molecular pattern molecules.

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“…Peltz and colleagues in their study observed thirty times elevation of plasma HMGB1 levels after trauma compared to healthy controls during 1 h period of injury, which stabilized at 2 -6 h post-injury [20]. Cohen and colleagues found a compelling distinction in plasma levels of HMGB1 among survivors and nonsurvivors from severe trauma.…”

Section: Hmgb1 As a Biomarkermentioning

confidence: 96%

High Mobility Group Box 1 and Traumatic Brain Injury

Richard¹,

Wu²,

Su³

et al. 2017

JBBS

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Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. We identify High Mobility Group Box 1 (HMGB1) as a novel causative factor in the development of cerebral oedema, mediating coagulation, preventing secondary brain damage as well as serving as a novel therapeutic target to limit secondary neurological injury after TBI. As a prototypical danger associated molecular patterns (DAMP), HMGB1 is released from necrotic neurons via a NR2B-mediated mechanism during TBI. The secretion of HMGB1 requires severe injury and tissue hypoperfusion, and is associated with posttraumatic coagulation abnormalities, activation of complement and severe systemic inflammatory response. HMGB1 is clinically associated with elevated intracranial pressure (ICP) in patients and functionally promoted cerebral edema after TBI. The detrimental effects of HMGB1 is mediated at least in part between activation of microglial toll-like receptor 4 (TLR4) and the subsequent expression of the astrocytic water channel aquaporin-4 (AQP4). Anti-HMGB1mAb remarkably inhibited fluid percussion-induced brain edema by inhibiting HMGB1 translocation, protection of blood-brain barrier (BBB) integrity, suppression of inflammatory molecule expression and improvement of motor function. Our review demonstrates the pathological role of HMGB1 as well as the possible therapeutic valve of HMGB1 in patients with TBI.

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Hmgb1 Is Markedly Elevated Within 6 Hours of Mechanical Trauma in Humans

Cited by 172 publications

References 28 publications

The receptor for advanced glycation end products mediates lung endothelial activation by RBCs

The receptor for advanced glycation end products mediates lung endothelial activation by RBCs

Tissue damage negatively regulates LPS-induced macrophage necroptosis

High Mobility Group Box 1 and Traumatic Brain Injury

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