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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL126788-03
Application #
9386762
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Reineck, Lora A
Project Start
2015-12-15
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104