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  1. Article ; Online: RAGE interacts with the necroptotic protein RIPK3 and mediates transfusion-induced danger signal release.

    Faust, Hilary / Lam, Lk Metthew / Hotz, Meghan J / Qing, Danielle / Mangalmurti, Nilam S

    Vox sanguinis

    2020  Volume 115, Issue 8, Page(s) 729–734

    Abstract: RBC transfusion is associated with increased morbidity and mortality in critically ill patients. Endothelial cell necroptosis and subsequent damage-associated molecular pattern (DAMP) release has been identified as a mechanism of injury following RBC ... ...

    Abstract RBC transfusion is associated with increased morbidity and mortality in critically ill patients. Endothelial cell necroptosis and subsequent damage-associated molecular pattern (DAMP) release has been identified as a mechanism of injury following RBC transfusion. Mounting evidence implicates the pro-inflammatory pattern recognition receptor, Receptor for Advanced Glycation End Products (RAGE), in initiating cell death programmes such as necroptosis. Here, we demonstrate the role of RAGE in endothelial necroptosis, as deletion of RAGE attenuates necroptotic cell death in response to TNFα, LPS or CpG-DNA. We show direct interaction of RAGE with the critical mediator of necroptosis, Receptor Interacting Protein Kinase 3 (RIPK3), during necroptosis. Furthermore, we observe decreased plasma High Mobility Group Box 1 (HMGB1) and RIPK3 levels in RAGE deficient mice compared to WT mice post-transfusion, substantiating the role for RAGE in transfusion-induced DAMP release in vivo. Collectively, these findings underscore RAGE as an essential mediator of regulated necrosis and post-transfusion DAMP release. Further studies to understand the role of RAGE and the necroptotic pathway in transfusion-induced organ injury may offer key targets to mitigate transfusion-related risks, including the risk of ARDS, in susceptible hosts.
    MeSH term(s) Animals ; Endothelial Cells/physiology ; Erythrocyte Transfusion/adverse effects ; Female ; HMGB1 Protein ; Mice ; Mice, Inbred C57BL ; Necrosis/etiology ; Necrosis/metabolism ; Receptor for Advanced Glycation End Products/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Signal Transduction ; Tumor Necrosis Factor-alpha/metabolism
    Chemical Substances HMGB1 Protein ; Receptor for Advanced Glycation End Products ; Tumor Necrosis Factor-alpha ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ripk3 protein, mouse (EC 2.7.11.1)
    Language English
    Publishing date 2020-07-07
    Publishing country England
    Document type Journal Article
    ZDB-ID 80313-3
    ISSN 1423-0410 ; 0042-9007
    ISSN (online) 1423-0410
    ISSN 0042-9007
    DOI 10.1111/vox.12946
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 74: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: A microengineered model of RBC transfusion-induced pulmonary vascular injury.

    Seo, Jeongyun / Conegliano, David / Farrell, Megan / Cho, Minseon / Ding, Xueting / Seykora, Thomas / Qing, Danielle / Mangalmurti, Nilam S / Huh, Dongeun

    Scientific reports

    2017  Volume 7, Issue 1, Page(s) 3413

    Abstract: Red blood cell (RBC) transfusion poses significant risks to critically ill patients by increasing their susceptibility to acute respiratory distress syndrome. While the underlying mechanisms of this life-threatening syndrome remain elusive, studies ... ...

    Abstract Red blood cell (RBC) transfusion poses significant risks to critically ill patients by increasing their susceptibility to acute respiratory distress syndrome. While the underlying mechanisms of this life-threatening syndrome remain elusive, studies suggest that RBC-induced microvascular injury in the distal lung plays a central role in the development of lung injury following blood transfusion. Here we present a novel microengineering strategy to model and investigate this key disease process. Specifically, we created a microdevice for culturing primary human lung endothelial cells under physiological flow conditions to recapitulate the morphology and hemodynamic environment of the pulmonary microvascular endothelium in vivo. Perfusion of the microengineered vessel with human RBCs resulted in abnormal cytoskeletal rearrangement and release of intracellular molecules associated with regulated necrotic cell death, replicating the characteristics of acute endothelial injury in transfused lungs in vivo. Our data also revealed the significant effect of hemodynamic shear stress on RBC-induced microvascular injury. Furthermore, we integrated the microfluidic endothelium with a computer-controlled mechanical stretching system to show that breathing-induced physiological deformation of the pulmonary microvasculature may exacerbate vascular injury during RBC transfusion. Our biomimetic microsystem provides an enabling platform to mechanistically study transfusion-associated pulmonary vascular complications in susceptible patient populations.
    MeSH term(s) Cells, Cultured ; Endothelium, Vascular/cytology ; Endothelium, Vascular/injuries ; Erythrocyte Transfusion/adverse effects ; Hemodynamics ; Humans ; Lung Injury/etiology ; Lung Injury/pathology ; Microfluidics/methods ; Pulmonary Circulation ; Stress, Mechanical
    Language English
    Publishing date 2017-06-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-017-03597-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain Quiescence and to Prevent Lung Injury.

    Hotz, Meghan J / Qing, Danielle / Shashaty, Michael G S / Zhang, Peggy / Faust, Hilary / Sondheimer, Neal / Rivella, Stefano / Worthen, G Scott / Mangalmurti, Nilam S

    American journal of respiratory and critical care medicine

    2017  Volume 197, Issue 4, Page(s) 470–480

    Abstract: Rationale: Potentially hazardous CpG-containing cell-free mitochondrial DNA (cf-mtDNA) is routinely released into the circulation and is associated with morbidity and mortality in critically ill patients. How the body avoids inappropriate innate immune ... ...

    Abstract Rationale: Potentially hazardous CpG-containing cell-free mitochondrial DNA (cf-mtDNA) is routinely released into the circulation and is associated with morbidity and mortality in critically ill patients. How the body avoids inappropriate innate immune activation by cf-mtDNA remains unknown. Because red blood cells (RBCs) modulate innate immune responses by scavenging chemokines, we hypothesized that RBCs may attenuate CpG-induced lung inflammation through direct scavenging of CpG-containing DNA.
    Objectives: To determine the mechanisms of CpG-DNA binding to RBCs and the effects of RBC-mediated DNA scavenging on lung inflammation.
    Methods: mtDNA on murine RBCs was measured under basal conditions and after systemic inflammation. mtDNA content on human RBCs from healthy control subjects and trauma patients was measured. Toll-like receptor 9 (TLR9) expression on RBCs and TLR9-dependent binding of CpG-DNA to RBCs were determined. A murine model of RBC transfusion after CpG-DNA-induced lung injury was used to investigate the role of RBC-mediated DNA scavenging in mitigating lung injury in vivo.
    Measurements and main results: Under basal conditions, RBCs bind CpG-DNA. The plasma-to-RBC mtDNA ratio is low in naive mice and in healthy volunteers but increases after systemic inflammation, demonstrating that the majority of cf-mtDNA is RBC-bound under homeostatic conditions and that the unbound fraction increases during inflammation. RBCs express TLR9 and bind CpG-DNA through TLR9. Loss of TLR9-dependent RBC-mediated CpG-DNA scavenging increased lung injury in vivo.
    Conclusions: RBCs homeostatically bind mtDNA, and RBC-mediated DNA scavenging is essential in mitigating lung injury after CpG-DNA. Our data suggest a role for RBCs in regulating lung inflammation during disease states where cf-mtDNA is elevated, such as sepsis and trauma.
    MeSH term(s) Adolescent ; Adult ; Aged ; Animals ; DNA, Mitochondrial/blood ; DNA, Mitochondrial/immunology ; Disease Models, Animal ; Erythrocytes/immunology ; Erythrocytes/physiology ; Female ; Homeostasis ; Humans ; Lung Injury/blood ; Lung Injury/etiology ; Lung Injury/prevention & control ; Male ; Mice ; Middle Aged ; Pneumonia/blood ; Pneumonia/complications ; Pneumonia/prevention & control ; Reference Values ; Toll-Like Receptor 9/blood ; Toll-Like Receptor 9/genetics ; Toll-Like Receptor 9/immunology ; Young Adult
    Chemical Substances DNA, Mitochondrial ; TLR9 protein, human ; Tlr9 protein, mouse ; Toll-Like Receptor 9
    Language English
    Publishing date 2017-10-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1180953-x
    ISSN 1535-4970 ; 0003-0805 ; 1073-449X
    ISSN (online) 1535-4970
    ISSN 0003-0805 ; 1073-449X
    DOI 10.1164/rccm.201706-1161OC
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh II Zs.80: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
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  4. Article ; Online: Plasma Levels of Receptor Interacting Protein Kinase-3 (RIP3), an Essential Mediator of Necroptosis, are Associated with Acute Kidney Injury in Critically Ill Trauma Patients.

    Shashaty, Michael G S / Reilly, John P / Sims, Carrie A / Holena, Daniel N / Qing, Danielle / Forker, Caitlin M / Hotz, Meghan J / Meyer, Nuala J / Lanken, Paul N / Feldman, Harold I / Christie, Jason D / Mangalmurti, Nilam S

    Shock (Augusta, Ga.)

    2016  Volume 46, Issue 2, Page(s) 139–143

    Abstract: Background: Receptor interacting protein kinase-3 (RIP3) is a key mediator of necroptosis, a form of regulated cell death recently implicated in murine models of renal ischemia-reperfusion injury and transfusion-associated endothelial injury. The ... ...

    Abstract Background: Receptor interacting protein kinase-3 (RIP3) is a key mediator of necroptosis, a form of regulated cell death recently implicated in murine models of renal ischemia-reperfusion injury and transfusion-associated endothelial injury. The importance of necroptosis in human AKI is unknown. We hypothesized that plasma RIP3 concentrations would be associated with acute kidney injury (AKI) after severe trauma.
    Methods: We performed a case-control study nested in a prospective cohort of critically ill trauma patients. AKI was defined by AKI Network creatinine criteria within 6 days of presentation. Of 158 cohort subjects, we selected 13 who developed AKI stage 2 or 3, 27 with AKI stage 1, and 40 without AKI. We compared plasma RIP3 concentrations across these groups at presentation and 48 h. Since red blood cell (RBC) transfusion is an AKI risk factor, we also tested the association of RBCs transfused during resuscitation with RIP3 levels.
    Results: Median plasma RIP3 concentration rose more than 10-fold from presentation (15.6 (interquartile range 15.6-41.3) pg/mL) to 48 h (164.7 (66.9-300.6) pg/mL; P <0.001). RIP3 concentrations at 48 h were associated with AKI stage (no AKI: 144.8 (58.6-234.9) pg/mL; AKI stage 1: 165.8 (43.0-310.9) pg/mL; AKI stage 2-3: 365.5 (155.1-727.5) pg/mL; P = 0.010) whereas this association was not seen at presentation (P = 0.324). RBC transfusions were also associated with 48-h plasma RIP3 (no RBCs: 99.4 (15.6-166.1) pg/mL; 1-5 units: 182.6 (98.5-274.1) pg/mL; >5 units: 341.8 (150.1-423.8) pg/mL; P <0.001).
    Conclusions: In critically ill trauma patients, plasma levels of the necroptosis mediator RIP3 at 48 h were associated with AKI stage and RBC transfusions.
    Language English
    Publishing date 2016-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1185432-7
    ISSN 1540-0514 ; 1073-2322
    ISSN (online) 1540-0514
    ISSN 1073-2322
    DOI 10.1097/SHK.0000000000000596
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3985: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Red blood cells induce necroptosis of lung endothelial cells and increase susceptibility to lung inflammation.

    Qing, Danielle Y / Conegliano, David / Shashaty, Michael G S / Seo, Jeongyun / Reilly, John P / Worthen, G Scott / Huh, Dongeun / Meyer, Nuala J / Mangalmurti, Nilam S

    American journal of respiratory and critical care medicine

    2014  Volume 190, Issue 11, Page(s) 1243–1254

    Abstract: Rationale: Red blood cell (RBC) transfusions are associated with increased risk of acute respiratory distress syndrome (ARDS) in the critically ill, yet the mechanisms for enhanced susceptibility to ARDS conferred by RBC transfusions remain unknown.: ... ...

    Abstract Rationale: Red blood cell (RBC) transfusions are associated with increased risk of acute respiratory distress syndrome (ARDS) in the critically ill, yet the mechanisms for enhanced susceptibility to ARDS conferred by RBC transfusions remain unknown.
    Objectives: To determine the mechanisms of lung endothelial cell (EC) High Mobility Group Box 1 (HMGB1) release following exposure to RBCs and to determine whether RBC transfusion increases susceptibility to lung inflammation in vivo through release of the danger signal HMGB1.
    Methods: In vitro studies examining human lung EC viability and HMGB1 release following exposure to allogenic RBCs were conducted under static conditions and using a microengineered model of RBC perfusion. The plasma from transfused and nontransfused patients with severe sepsis was examined for markers of cellular injury. A murine model of RBC transfusion followed by LPS administration was used to determine the effects of RBC transfusion and HMGB1 release on LPS-induced lung inflammation.
    Measurements and main results: After incubation with RBCs, lung ECs underwent regulated necrotic cell death (necroptosis) and released the essential mediator of necroptosis, receptor-interacting serine/threonine-protein kinase 3 (RIP3), and HMGB1. RIP3 was detectable in the plasma of patients with severe sepsis, and was increased with blood transfusion and among nonsurvivors of sepsis. RBC transfusion sensitized mice to LPS-induced lung inflammation through release of the danger signal HMGB1.
    Conclusions: RBC transfusion enhances susceptibility to lung inflammation through release of HMGB1 and induces necroptosis of lung EC. Necroptosis and subsequent danger signal release is a novel mechanism of injury following transfusion that may account for the increased risk of ARDS in critically ill transfused patients.
    MeSH term(s) Animals ; Critical Illness ; Disease Models, Animal ; Endothelial Cells/pathology ; Erythrocyte Transfusion/adverse effects ; HMGB1 Protein/immunology ; HMGB1 Protein/physiology ; Humans ; In Vitro Techniques ; Lung/pathology ; Mice ; Middle Aged ; Necrosis ; Pneumonia/etiology ; Respiratory Distress Syndrome/etiology
    Chemical Substances HMGB1 Protein
    Language English
    Publishing date 2014-11-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1180953-x
    ISSN 1535-4970 ; 0003-0805 ; 1073-449X
    ISSN (online) 1535-4970
    ISSN 0003-0805 ; 1073-449X
    DOI 10.1164/rccm.201406-1095OC
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uh II Zs.80: Show issues Location:
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