Red blood cell (RBC) transfusions are a common therapy utilized in hospitals, with ~15 million RBC units administered annually in the United States. RBC transfusions are associated with multiple adverse effects, including an increased risk for bacterial infection. Before transfusion, donor RBCs are refrigerator-stored for up to 42 days, as established by FDA criteria. During storage, RBCs undergo multiple structural and metabolic alterations, collectively known as ?the storage lesion.? As a result, some storage-damaged RBCs are rapidly cleared from the circulation post-transfusion, a process mediated predominantly by phagocytic cells in the spleen and liver (i.e., ?extravascular hemolysis?). Although several studies were designed to observe the incidence of adverse effects following transfusions of stored RBCs, very little is known about the underlying mechanisms causing these adverse effects. Therefore, to identify potential mechanisms, we will use a novel mouse model of RBC storage and clearance. Our Laboratory has successfully used this model previously and observed that mice are more susceptible to bacterial infection following transfusions of storage-damaged RBCs, which are cleared by extravascular hemolysis. Therefore, we believe that mouse models offer tremendous potential for achieving the overall aim of this project, which is to investigate the mechanism(s) by which hemolysis leads to an increased risk of bacterial infections, with our overall hypothesis being that robust erythrophagocytosis by macrophages impairs bacterial phagocytosis during a subsequent infection.
The proposed research investigates the potential mechanisms for impaired bacterial clearance following a transfusion of storage-damaged (?old?) red blood cells (RBCs). Although RBC transfusions are a very common and beneficial therapy used by hospitals, very little is known regarding potential mechanisms underlying various observed adverse effects, including the increased risk of bacterial infection. This project uses a novel mouse model for generating blood banks that are refrigerator-stored to mimic the damage that occurs to human RBCs prior to transfusions, followed by subsequent bacterial infections with E. coli and S. aureus, two important human pathogens. The results obtained from this project will have tremendous clinical relevance for the field of transfusion medicine.
| Youssef, Lyla A; Rebbaa, Abdelhadi; Pampou, Sergey et al. (2018) Increased erythrophagocytosis induces ferroptosis in red pulp macrophages in a mouse model of transfusion. Blood 131:2581-2593 |
