Red blood cell (RBC) transfusion is the most common therapeutic intervention employed to maintain and/or improve tissue and end-organ oxygen delivery. Despite the conceptual simplicity of this treatment recent studies indicate that allogenic RBC infusion often produces little clinical benefit and may actually harm the recipient. We recently determined that storage of human blood leads to rapid losses in nitric oxide (NO) bioactivity (S-nitroso-hemoglobin) that are precisely paralleled by losses in the ability of stored RBCs to dilate blood vessels and thereby deliver oxygen. We further showed that by replenishing NO bioactivity, the defect was corrected. We have now also found that prolonged storage leads to a defect in the regeneration of S-nitroso-hemoglobion (i.e. evident with older blood), which is at least partly reversible. This novel mechanism for the loss of physiological activity in banked blood and, more importantly, a putative intervention for its correction, raise the possibility that restoration of NO bioactivity prior to administration of packed RBCs may significantly ameliorate transfusion-associated ischemic morbidity. Our findings have led to the present grant application in which we will test the following hypothesis: Renitrosylation to increase S-nitroso-hemoglobin content restores the hypoxic-vasodilatory activity of stored RBCs to improve tissue oxygen delivery and physiologic status during transfusion. Research Objectives: 1. To optimize and validate in vitro methods of large-scale renitrosylation that restore hypoxic- vasodliatory activity to banked RBCs independent of blood group and across storage conditions;and 2. To conduct focused in vivo assessments to demonstrate the benefits of pre-transfusion renitrosylation on blood flow and local oxygen delivery. Through the proposed series of bench top, pre-clinical, and clinical experiments detailed herein, we will establish large-scale methodology to renitrosylate stored blood and thoroughly assess the physiological benefits. We anticipate that the information generated from these studies may affect fundamental changes in clinical care. Restoration of NO bioactivity and oxygen delivery capabilities of stored RBCs will result in blood transfusion achieving its clinical purpose: vasodilation in the micro-circulation to maintain or enhance end- organ oxygen delivery in the anemic patient. Renitrosylation would be a novel therapeutic intervention, extremely easy to implement, that could yield significant clinical benefits and economic savings.

Public Health Relevance

Blood transfusion is among the most commonly performed medical procedures: each year approximately 5 million Americans receive 14 million units of packed red blood cells (RBCs) to treat anemia resulting from a variety of acute causes and chronic disease states. However, it is now recognized that the administration of packed RBCs may not only fail to improve oxygen delivery but may actually worsen ischemia. Based on the proposition that an impairment in the vasodilatory ability of RBCs (resulting from storage-related depletion of nitric oxide bioactivity) contributes substantially to transfusion-related morbidity, we propose to generate methods for the restoration of RBC nitric oxide bioactivity in clinical settings, and to determine whether restoration of RBC vasodilation ameliorates the deleterious effects of transfusion.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095463-04
Application #
8122380
Study Section
Special Emphasis Panel (ZHL1-CSR-S (S1))
Program Officer
Welniak, Lisbeth A
Project Start
2009-09-16
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$392,500
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Lai, Thung-S; Lindberg, Robert A; Zhou, Hua-Lin et al. (2017) Endothelial cell-surface tissue transglutaminase inhibits neutrophil adhesion by binding and releasing nitric oxide. Sci Rep 7:16163
Matto, Faisal; Kouretas, Peter C; Smith, Richard et al. (2017) S-Nitrosohemoglobin Levels and Patient Outcome After Transfusion During Pediatric Bypass Surgery. Clin Transl Sci :
Zhang, Rongli; Hess, Douglas T; Qian, Zhaoxia et al. (2015) Hemoglobin ?Cys93 is essential for cardiovascular function and integrated response to hypoxia. Proc Natl Acad Sci U S A 112:6425-30
Wagner, Stephen J; Glynn, Simone A; Welniak, Lisbeth A et al. (2014) Research opportunities in optimizing storage of red blood cell products. Transfusion 54:483-94
Reynolds, James D; Bennett, Kyla M; Cina, Anthony J et al. (2013) S-nitrosylation therapy to improve oxygen delivery of banked blood. Proc Natl Acad Sci U S A 110:11529-34
Haldar, Saptarsi M; Stamler, Jonathan S (2013) S-nitrosylation: integrator of cardiovascular performance and oxygen delivery. J Clin Invest 123:101-10
Seth, Divya; Hausladen, Alfred; Wang, Ya-Juan et al. (2012) Endogenous protein S-Nitrosylation in E. coli: regulation by OxyR. Science 336:470-3
Cutler, Michael J; Plummer, Bradley N; Wan, Xiaoping et al. (2012) Aberrant S-nitrosylation mediates calcium-triggered ventricular arrhythmia in the intact heart. Proc Natl Acad Sci U S A 109:18186-91
Hess, Douglas T; Stamler, Jonathan S (2012) Regulation by S-nitrosylation of protein post-translational modification. J Biol Chem 287:4411-8
Anand, Puneet; Stamler, Jonathan S (2012) Enzymatic mechanisms regulating protein S-nitrosylation: implications in health and disease. J Mol Med (Berl) 90:233-44

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