The long term goal of our proposal is to understand the mechanisms by which transfusion of older packed red blood cell (pRBC) units worsens patient outcomes after resuscitation from hemorrhage. Hemorrhagic shock is the most common cause of potentially preventable death after trauma. Current resuscitation strategies for patients with significant blood loss include the use pRBCs and fresh-frozen plasma. While the use of pRBCs for resuscitation of the injured patient is essential for survival, transfusion of pRBC units that have aged during storage is associated with worsened clinical outcomes in patients, including increased risk of multisystem organ failure, pneumonia, renal failure, sepsis, and death. We have demonstrated that microparticles from aged pRBC units contain red blood cell microparticles that mediate inflammatory events after transfusion. Our previous studies and preliminary data strongly indicate that microparticle formation is a key event during pRBC storage and that pRBC microparticles are critical mediators of lung inflammation after resuscitation from hemorrhage. In the current proposal, we hypothesize that microparticles from stored packed red blood cells are acutely pro-inflammatory in nature and promote inflammatory consequences, such as endothelial cell activation, formation of pulmonary microthrombi, and development of lung inflammation after resuscitation from hemorrhage. To test this hypothesis, we propose the following specific aims:
Aim 1 : Test mechanistic strategies to reduce pRBC microparticle generation during storage and mitigate pro-inflammatory potential of stored pRBC units;
Aim 2 : Determine the molecular mechanisms of endothelial cell activation by microparticles from stored pRBC units;
Aim 3 : Determine the mechanisms by which pRBC microparticles promote multi-cellular interactions leading pulmonary microthrombi after hemorrhage and resuscitation. The proposed studies will general novel data concerning the role of microparticles from stored pRBC units and the development of endothelial cell dysfunction after hemorrhage and resuscitation. If successful, these studies will identify new therapeutic targets allowing improved clinical outcomes after hemorrhage and resuscitation with stored pRBC units.

Public Health Relevance

Hemorrhage is a major cause of death in injured patients. Treatment to improve survival from hemorrhage include transfusion of stored packed red blood cells, which may cause harm to patients who survive. The proposed experiments will increase our understanding of microparticle formation during packed red blood cell storage, the underlying mechanisms of resulting endothelial cell activation and pulmonary thrombosis, and potentially allow mitigation of harm from the use of stored packed red blood cells in resuscitation from hemorrhage.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM107625-06A1
Application #
9738208
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Zhao, Xiaoli
Project Start
2014-02-01
Project End
2023-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Surgery
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Kim, Young; Abplanalp, William A; Jung, Andrew D et al. (2018) Endocytosis of Red Blood Cell Microparticles by Pulmonary Endothelial Cells is Mediated By Rab5. Shock 49:288-294
Richter, Jillian R; Sutton, Jeffrey M; Hexley, Phillip et al. (2018) Leukoreduction of packed red blood cells attenuates proinflammatory properties of storage-derived microvesicles. J Surg Res 223:128-135
Kim, Young; Xia, Brent T; Jung, Andrew D et al. (2018) Microparticles from stored red blood cells promote a hypercoagulable state in a murine model of transfusion. Surgery 163:423-429
Hoehn, Richard S; Jernigan, Peter L; Japtok, Lukasz et al. (2017) Acid Sphingomyelinase Inhibition in Stored Erythrocytes Reduces Transfusion-Associated Lung Inflammation. Ann Surg 265:218-226
Chang, Alex L; Kim, Young; Seitz, Aaron P et al. (2017) Erythrocyte-Derived Microparticles Activate Pulmonary Endothelial Cells in a Murine Model of Transfusion. Shock 47:632-637
Chang, Alex; Kim, Young; Hoehn, Richard et al. (2017) Cryopreserved packed red blood cells in surgical patients: past, present, and future. Blood Transfus 15:341-347
Chang, Alex L; Kim, Young; Seitz, Aaron P et al. (2017) pH modulation ameliorates the red blood cell storage lesion in a murine model of transfusion. J Surg Res 212:54-59
Kim, Young; Jung, Andrew D; Pritts, Timothy A (2017) Age before duty: the effect of storage duration on mortality after red blood cell transfusion. J Thorac Dis 9:441-443
Hoehn, Richard S; Jernigan, Peter L; Chang, Alex L et al. (2016) Acid Sphingomyelinase Inhibition Prevents Hemolysis During Erythrocyte Storage. Cell Physiol Biochem 39:331-40
Kim, Young; Xia, Brent T; Chang, Alex L et al. (2016) Role of Leukoreduction of Packed Red Blood Cell Units in Trauma Patients: A Review. Int J Hematol Res 2:124-129

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