Systemic Ubiquitin Release After Blunt Trauma and Burns: Association With Injury Severity, Posttraumatic Complications, and Survival

Majetschak, Matthias; Zedler, Siegfried; Hostmann, Arwed; Sorell, Luis; Patel, Mayur B.; Novar, Lissette T.; Kraft, Robert A.; Habib, Fahim; Moya, Marc A. de; Ertel, Wolfgang; Faist, Eugen; Schade, Ulrich

doi:10.1097/ta.0b013e3181641bc5

Cited by 22 publications

(44 citation statements)

References 36 publications

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“…The observation that i.v. AMD3100 did not affect ubiquitin plasma levels further supports the assumption that the majority of extracellular ubiquitin originates from its passive release from cells and tissues undergoing physiological turnover or damage (16)(17)(18)37,56).…”

Section: Discussionsupporting

confidence: 53%

“…Furthermore, we observed that high systemic ubiquitin levels are associated with a lower degree of organ dysfunction and reduced mortality in burn patients, suggesting that endogenous extracellular ubiquitin mediates protective effects during the initial inflammatory response to tissue injury (17). Although the regulation of SDF-1α levels after trauma and its association with clinical outcomes are largely unknown, administration of SDF-1α and of various SDF-1α mimetic proteins have been shown to result in beneficial effects in models of acute infectious and sterile inflammation in vivo (18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 84%

“…AMD3100 (generic name Plerixafor) was approved by the U.S. Food and Drug Administration to be used in combination with granulocytecolony stimulating factor to mobilize hematopoietic stem cells to the bloodstream in patients with non-Hodgkin lymphoma and multiple myeloma (36). On the basis of available data on the role of endogenous extracellular ubiquitin after trauma in patients (16,17), its inhibitory effects on leukocyte function upon pattern recognition receptor (PRR) activation (16,25,37) and the therapeutically relevant actions of CXCR4 agonists in various animal models (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), we hypothesized that blockade of ligand binding to CXCR4 will enhance proinflammatory responses of leukocytes and result in adverse effects when animals are subjected to severe trauma. Thus, we studied the pathophysiological response to trauma after blockade of CXCR4 with AMD3100 in a large animal model, which was designed to mimic the typical blunt polytrauma patient.…”

Section: Initial Assessment Of the Role Of CXC Chemokine Receptor 4 Amentioning

confidence: 99%

“…Ubiquitin plasma concentrations were measured with an indirect competitive ELISA, as described previously (17,25). The lower detection limit was 11 ng/mL.…”

Section: Elisasmentioning

confidence: 99%

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Initial Assessment of the Role of CXC Chemokine Receptor 4 after Polytrauma

Bach

Saini

Baker

et al. 2012

Mol Med

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CXC chemokine receptor (CXCR)-4 agonists have been shown to attenuate inflammation and organ injury in various disease models, including trauma/hemorrhage. The pathophysiological role of CXCR4 during the early response to tissue injury, however, remains unknown. Therefore, we investigated the effects of AMD3100, a drug that antagonizes binding of stromal cell-derived factor (SDF)-1α and ubiquitin to CXCR4 during the initial response to polytrauma in pigs. Fifteen minutes before polytrauma (femur fractures/lung contusion; control: sham), 350 nmol/kg AMD3100, equimolar AMD3100 and ubiquitin (350 nmol/kg each) or vehicle were administered intravenously. After a 60-min shock period, fluid resuscitation was performed for 360 min. Ubiquitin binding to peripheral blood mononuclear cells was significantly reduced after intravenous AMD3100. SDF-1α plasma levels increased transiently >10-fold with AMD3100 in all animals. In injured animals, AMD3100 increased fluid requirements to maintain hemodynamics and enhanced increases in peripheral blood granulocytes, lymphocytes and monocytes, compared with its effects in uninjured animals. Cytokine release from leukocytes in response to Toll-like receptor (TLR)-2 and TLR-4 activation was increased after in vitro AMD3100 treatment of normal whole blood and after in vivo AMD3100 administration in animals subjected to polytrauma. Coadministration of AMD3100/ubiquitin reduced lactate levels, prevented AMD3100-induced increases in fluid requirements and sensitization of the tumor necrosis factor (TNF)-α and interleukin (IL)-6 release upon TLR-2/4 activation, but did not attenuate increases in leukocyte counts and SDF-1α plasma levels. Our findings suggest that CXCR4 controls leukocyte mobilization after trauma, regulates leukocyte reactivity toward inflammatory stimuli and mediates protective effects during the early phase of trauma-induced inflammation.

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Section: Discussionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 84%

Section: Initial Assessment Of the Role Of CXC Chemokine Receptor 4 Amentioning

confidence: 99%

“…Ubiquitin plasma concentrations were measured with an indirect competitive ELISA, as described previously (17,25). The lower detection limit was 11 ng/mL.…”

Section: Elisasmentioning

confidence: 99%

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Initial Assessment of the Role of CXC Chemokine Receptor 4 after Polytrauma

Bach

Saini

Baker

et al. 2012

Mol Med

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“…Along with the observation that lower systemic ubiquitin levels were accompanied by a higher degree of organ dysfunction and failure (13), these data suggested that ubiquitin release after trauma is beneficial and may function to limit exuberant inflammation. Accordingly, we showed in a series of in vivo studies that treatment with exogenous ubiquitin is anti-inflammatory and immunosuppressive and that ubiquitin administration is neuroprotective and reduces organ injury after endotoxic shock, trauma, and ischemia-reperfusion (14 -19).…”

mentioning

confidence: 81%

CXC Chemokine Receptor 4 Is a Cell Surface Receptor for Extracellular Ubiquitin

Saini

Marchese

Majetschak

2010

Journal of Biological Chemistry

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152

204

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Ubiquitin is one of the most highly conserved proteins in eukaryotes and plays major biological roles as a post-translational protein modifier. Ubiquitin is also a natural constituent of plasma, and several lines of evidence suggest that extracellular ubiquitin is an immune modulator with anti-inflammatory properties. In addition, ubiquitin treatment has been shown to limit inflammation and reduce organ injury in various disease models and species in vivo. However, its mechanism of action is unknown. Here we show that extracellular ubiquitin is a natural CXC chemokine receptor 4 (CXCR4 and CD184) agonist. Extracellular ubiquitin promotes intracellular Ca 2؉ flux and reduces cAMP levels through a G protein-coupled receptor that signals via a G␣ i/o protein in THP1 cells. Toll-like receptor 4 stimulation reduces ubiquitin-binding sites, which enabled identification of four G␣ i/o PCRs as ubiquitin receptor candidates. Overexpression of candidate genes in HEK293 cells, gene silencing in THP1 cells, competition binding, and signaling studies with the CXCR4 agonist stromal cell-derived factor-1␣ (chemokine (CXC motif) ligand 12) and inhibitor AMD3100 identify CXCR4 as a functional ubiquitin receptor. Our finding uncovers a fundamentally new aspect of the role of ubiquitin in biology, has implications for the understanding of CXCR4-mediated events, and is expected to facilitate development of new therapeutic avenues for a variety of diseases.

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Extracellular Ubiquitin: Role in Myocyte Apoptosis and Myocardial Remodeling

Scofield

Amin

Singh

et al. 2015

Comprehensive Physiology

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Ubiquitin (UB) is a highly conserved low molecular weight (8.5 kDa) protein. It consists of 76 amino acid residues and is found in all eukaryotic cells. The covalent linkage of UB to a variety of cellular proteins (ubiquitination) is one of the most common posttranslational modifications in eukaryotic cells. This modification generally regulates protein turnover and protects the cells from damaged or misfolded proteins. The polyubiquitination of proteins serves as a signal for degradation via the 26S proteasome pathway. UB is present in trace amounts in body fluids. Elevated levels of UB are described in the serum or plasma of patients under a variety of conditions. Extracellular UB is proposed to have pleiotropic roles including regulation of immune response, anti-inflammatory, and neuroprotective activities. CXCR4 is identified as receptor for extracellular UB in hematopoietic cells. Heart failure represents a major cause of morbidity and mortality in western society. Cardiac remodeling is a determinant of the clinical course of heart failure. The components involved in myocardial remodeling include-myocytes, fibroblasts, interstitium, and coronary vasculature. Increased sympathetic nerve activity in the form of norepinephrine is a common feature during heart failure. Acting via β-adrenergic receptor (β-AR), norepinephrine is shown to induce myocyte apoptosis and myocardial fibrosis. β-AR stimulation increases extracellular levels of UB in myocytes, and UB inhibits β-AR-stimulated increases in myocyte apoptosis and myocardial fibrosis. This review summarizes intracellular and extracellular functions of UB with particular emphasis on the role of extracellular UB in cardiac myocyte apoptosis and myocardial remodeling.

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Systemic Ubiquitin Release After Blunt Trauma and Burns: Association With Injury Severity, Posttraumatic Complications, and Survival

Cited by 22 publications

References 36 publications

Initial Assessment of the Role of CXC Chemokine Receptor 4 after Polytrauma

Initial Assessment of the Role of CXC Chemokine Receptor 4 after Polytrauma

CXC Chemokine Receptor 4 Is a Cell Surface Receptor for Extracellular Ubiquitin

Extracellular Ubiquitin: Role in Myocyte Apoptosis and Myocardial Remodeling

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