PROJECT SUMMARYThe therapeutic benefit of transfusion presumes a direct correlation between blood oxygen carrying capacityand oxygen delivery. However, studies have shown that stored blood loses its ability to oxygenate tissues. Thesequelae that can occur after transfusion (renal injury, myocardial infarction, death) are consistent with the ideathat banked blood may exacerbate rather than correct anemia-induced hypoxia.We have discovered that banked blood has markedly diminished levels of nitric oxide/S-nitrosothiol (NO/SNO)bioactivity including reduced amounts of the S-nitrosylated form of hemoglobin (SNO-Hb), a major mediator ofblood flow and peripheral oxygen delivery. This decline in SNO provides a mechanistic basis for the impairedvasodilatory activity of stored red blood cells (RBCs) and an explanation for why transfusion of even smallamounts of blood may impair tissue perfusion. We have built on this novel finding by demonstrating thatrestoration of SNO-Hb levels (renitrosylation) corrects storage-induced deficiencies in RBC oxygen deliveryand transfusion-induced organ dysfunction in multiple preclinical transfusion paradigms, and we have initiatedclinical studies to assess the effects of transfusion on human tissue oxygenation. We have also developedfirst-in-class renitrosylating agents that are already undergoing clinical testing.We are positioned to provide critically needed data on the effects of transfusion on tissue oxygenation inhumans and to advance the benefits of renitrosylation therapy on oxygen delivery through the following aims: 1. To advance understanding of the molecular mechanisms by which RBCs deploy SNO-based signals to regulate tissue oxygenation in fresh and stored blood. 2. To develop a device for ex vivo renitrosylation. 3. To determine if the physiologic responses to transfusion with renitrosylated RBCs are superior to untreated banked blood in a preclinical trauma model. 4. To conduct an autologous standard flow (i.e. non-trauma) transfusion study in humans with and without renitrosylation to delineate the physiologic effects of transfusion and the benefits of increased/restored SNO-Hb levels on tissue oxygenation.Collectively, our studies will provide much-needed insight into the effects of transfusion on tissue oxygenation,shed light on the mechanistic basis of adverse ischemic events associated with transfusion, and acceleratedevelopment of therapeutic approaches (repletion of SNO-Hb). Restoration of the oxygen delivery capabilitiesof banked blood should result in blood transfusion achieving its clinical purpose: vasodilation in themicrocirculation to improve end-organ oxygen delivery in the anemic patient. To the extent that the world'ssupplies of banked RBCs are deficient in SNO-Hb, renitrosylation may hold significant therapeutic promise.
|Effective start/end date||7/1/16 → 6/30/21|
- National Institutes of Health: $565,855.00
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