Acid Sphingomyelinase Inhibition in Stored Erythrocytes Reduces Transfusion-Associated Lung Inflammation

Hoehn, Richard S.; Jernigan, Peter L.; Japtok, Lukasz; Chang, Alex L.; Caldwell, Charles C.; Kleuser, Burkhard; Lentsch, Alex B.; Edwards, Michael J.; Gulbins, Erich; Pritts, Timothy A.

doi:10.1097/sla.0000000000001648

Cited by 35 publications

(39 citation statements)

References 51 publications

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“…14 In addition, previous work from our laboratory indicates that the microparticle concentration present in stored human pRBC units equals or exceeds the number of microparticles found in stored murine units. 30 Additionally, previous studies have shown that higher MP concentrations increase their biological effects in a dose-response fashion. 14 Thus, we suspect that potential harm from microparticles from stored pRBC units may become clinically relevant in patients who receive multiple units of pRBCs, especially in the setting of massive transfusion.…”

Section: Discussionmentioning

confidence: 99%

Erythrocyte-Derived Microparticles Activate Pulmonary Endothelial Cells in a Murine Model of Transfusion

Chang

Kim

Seitz

et al. 2017

Shock

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Erythrocyte-derived microparticles (MPs) are sub-micrometer, biologically active vesicles shed by red blood cells as part of the biochemical changes that occur during storage. We hypothesized that MPs from stored red blood cells would activate endothelial cells. MPs from aged murine packed red blood cells (pRBCs) were isolated and used to treat confluent layers of cultured endothelial cells. Endothelial expression of leukocyte adhesion molecules, ELAM-1 and ICAM-1, and inflammatory mediator, IL-6, were evaluated at 0.5, 6, 12, and 24 hours of treatment. Healthy C57BL/6 mice were transfused with a MP suspension and lung sections were analyzed for adhesion molecules and sequestered interstitial leukocytes. Increased levels of ELAM-1 and ICAM-1 were found on cultured endothelial cells 6 hours after MP stimulation (6.91 vs 4.07 relative fluorescent intensity, RFI, p<0.01, and 5.85 vs 3.55 RFI, p=0.01, respectively). IL-6 in cell culture supernatants was increased after 12 hours of MP stimulation compared to controls (1.24 vs 0.73 ng/ml, p=0.03). In vivo experiments demonstrated that MP injection increased ELAM-1 and ICAM-1 expression at 1 hour (18.56 vs 7.08 RFI, p<0.01, and 23.66 vs 6.87 RFI, p<0.01, respectively) and caused increased density of pulmonary interstitial leukocytes by 4 hours of treatment (69.25 vs 29.25 cells/HPF, p<0.01). This series of experiments supports our hypothesis that erythrocyte-derived MPs are able to activate pulmonary endothelium, leading to the pulmonary sequestration of leukocytes following the transfusion of stored pRBCs.

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Section: Discussionmentioning

confidence: 99%

Erythrocyte-Derived Microparticles Activate Pulmonary Endothelial Cells in a Murine Model of Transfusion

Chang

Kim

Seitz

et al. 2017

Shock

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“…For example, in C. elegans , inhibition of a lipid flippase that transfers phosphatidylethanolamine from the outer leaflet of the plasma membrane to the inner leaflet promotes vesicle budding [42,43]. Alterations in ceramide content on the outer leaflet via activation of acid sphingomyelinase can also induce membrane curvature and trigger microvesicle release [44–46]. Shedding of vesicles has been shown to occur from multiple aspects of the plasma membrane, including at microvillar protrusions of intestinal epithelial cells [47] and from cells engineered to overexpress hyaluronan synthase [48], as well as from cilia [49].…”

Section: Ev Biogenesis and Releasementioning

confidence: 99%

Extracellular Vesicles: Unique Intercellular Delivery Vehicles

Maas

Breakefield

Weaver

2017

Trends in Cell Biology

1,173

969

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Extracellular vesicles (EVs) are a heterogeneous collection of membrane-bound carriers with complex cargos, including proteins, lipids and nucleic acids. While release of EVs was previously thought to be only a mechanism to discard nonfunctional cellular components, increasing evidence implicates EVs as key players in intercellular and even interorganismal communication. EVs confer stability and can direct their cargoes to specific cell types. EV cargoes also appear to act in a combinatorial manner to communicate directives to other cells. This review will focus on recent findings and knowledge gaps in the area of EV biogenesis, release, and uptake. In addition, we highlight examples whereby EV cargoes control basic cellular functions, including motility and polarization, immune responses, and development, as well as contribute to diseases, such as cancer and neurodegeneration.

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“…Recent research has demonstrated that acid sphingomyelinase (Asm) activity in RBCs is associated with MP formation and treatment of RBCs with amitriptyline, an Asm inhibitor, inhibited MP formation during RBC storage. This treatment was associated with reduced lung inflammation following blood transfusion in a murine model (41). Together, these data demonstrate the significant contribution of RBC-derived MPs to immunomodulation after transfusion.…”

Section: Introductionmentioning

confidence: 99%

Balance Between the Proinflammatory and Anti-Inflammatory Immune Responses with Blood Transfusion in Sepsis

Rice

Pugh

Caldwell

et al. 2017

Critical Care Nursing Clinics of North America

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Acid Sphingomyelinase Inhibition in Stored Erythrocytes Reduces Transfusion-Associated Lung Inflammation

Abstract: Acid sphingomyelinase inhibition in stored pRBCs offers a novel mechanism for improving the quality of stored blood.

Cited by 35 publications

References 51 publications

Erythrocyte-Derived Microparticles Activate Pulmonary Endothelial Cells in a Murine Model of Transfusion

Erythrocyte-Derived Microparticles Activate Pulmonary Endothelial Cells in a Murine Model of Transfusion

Extracellular Vesicles: Unique Intercellular Delivery Vehicles

Balance Between the Proinflammatory and Anti-Inflammatory Immune Responses with Blood Transfusion in Sepsis

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