Recent epidemiologic studies have demonstrated increased morbidity, mortality, and the development of Acute Respiratory Distress Syndrome (ARDS) associated with red blood cell (RBC) transfusions in the critically ill, yet the mechanisms underlying this association remain unknown. Our data demonstrate that banked RBCs induce necroptosis (a form of regulated necrotic cell death) of lung endothelial cells and enhance susceptibility to subsequent injury. We have previously demonstrated that the proinflammatory receptor for advanced glycation endproducts (RAGE) mediates lung endothelial dysfunction following RBC transfusion. The overall goal of this proposal is to elucidate the role of RAGE in RBC-induced necroptosis.
In Specific Aim 1 the role of RAGE in sensing necroptotic stimuli will be examined in vitro and in a micro-engineered model of human lung.
Specific Aim 2 will explore the role of intracellular RAGE in necroptosis execution. Lastly, Specific Aim 3 will examine the in vivo effects of RBC- induced necroptosis on lung injury using animal models. Knowledge derived from these studies will elucidate some of the mechanisms by which RBCs enhance susceptibility to lung injury and hopefully lead to novel therapies to prevent the morbidity associated with RBC transfusions.

Public Health Relevance

Epidemiological studies have shown that red blood cell (RBC) transfusions are associated with increased morbidity and mortality and the development of Acute Respiratory Distress Syndrome (ARDS) in the critically ill. The etiology underlying this association remains uncertain, however the main goal of this study is to understand the mechanisms of necroptosis, one of the means by which RBC transfusions increase the risk of ARDS development in the critically ill. Completion of these studies will identify novel pathways of necroptosis, a mechanism of RBC-induced injury that may account for the enhanced risk of ARDS observed in critically ill transfusion recipients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Zhou, Guofei
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Hotz, Meghan J; Qing, Danielle; Shashaty, Michael G S et al. (2018) Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain Quiescence and to Prevent Lung Injury. Am J Respir Crit Care Med 197:470-480
Anderson, H Luke; Brodsky, Igor E; Mangalmurti, Nilam S (2018) The Evolving Erythrocyte: Red Blood Cells as Modulators of Innate Immunity. J Immunol 201:1343-1351
Seo, Jeongyun; Conegliano, David; Farrell, Megan et al. (2017) A microengineered model of RBC transfusion-induced pulmonary vascular injury. Sci Rep 7:3413
Shashaty, Michael G S; Reilly, John P; Sims, Carrie A et al. (2016) 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. Shock 46:139-43