The overall goal of this project is to improve the efficacy of transfusion of stored blood. There is good evidence that red blood cell storage results in loss of functionality and integrity of red blood cells over time and that this contributes to deleterious effects upon blood transfusion. This project is built around the hypothesis that this storage lesion is largely due to dysregulation of nitric oxide homeostasis in the blood. This disruption is due to increased nitric oxide scavenging by cell-free hemoglobin and microparticles that are released during hemolysis in stored blood and diminished nitric oxide production by the newly discovered red cell nitric oxide synthase. A vast array of clinical, biophysical, molecular biology, and biochemical tools will be applied to characterize the nitric oxide storage lesion in vitro in stored blood as well as in chimeric mice models, a canine model, and in human studies. In addition, therapeutics will be explored in these systems that could restore nitric oxide homeostasis by reducing nitric oxide scavenging and increasing nitric oxide production.

Public Health Relevance

(provided by applicant): There are several potential risks associated with transfusion of stored red blood cells, a procedure performed about 14 million times per year in patients undergoing surgery or with chronic illness. This project explores the hypothesis that deleterious effects of red cell transfusion are due to resulting upset in the availability of the important signaling molecule nitric oxide. The project investigates the cause of this reduction in nitric oxide bioavailability and explores ways to restore nitric oxide upon red cell transfusion.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098032-03
Application #
8106281
Study Section
Special Emphasis Panel (ZHL1-CSR-S (S1))
Program Officer
Welniak, Lisbeth A
Project Start
2009-09-18
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
3
Fiscal Year
2011
Total Cost
$688,267
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kim-Campbell, Nahmah; Gretchen, Catherine; Callaway, Clifton et al. (2017) Cell-Free Plasma Hemoglobin and Male Gender Are Risk Factors for Acute Kidney Injury in Low Risk Children Undergoing Cardiopulmonary Bypass. Crit Care Med 45:e1123-e1130
Meijles, Daniel N; Sahoo, Sanghamitra; Al Ghouleh, Imad et al. (2017) The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1. Sci Signal 10:
Gladwin, Mark T (2017) Translational Advances in the Field of Pulmonary Hypertension Bench to Bedside: How Fundamental Discoveries in Science Are Advancing Our Understanding and Therapy of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 195:1-3
Kato, Gregory J; Steinberg, Martin H; Gladwin, Mark T (2017) Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest 127:750-760
Suffredini, Dante A; Xu, Wanying; Sun, Junfeng et al. (2017) Parenteral irons versus transfused red blood cells for treatment of anemia during canine experimental bacterial pneumonia. Transfusion 57:2338-2347
Kanias, Tamir; Lanteri, Marion C; Page, Grier P et al. (2017) Ethnicity, sex, and age are determinants of red blood cell storage and stress hemolysis: results of the REDS-III RBC-Omics study. Blood Adv 1:1132-1141
Amdahl, Matthew B; Sparacino-Watkins, Courtney E; Corti, Paola et al. (2017) Efficient Reduction of Vertebrate Cytoglobins by the Cytochrome b5/Cytochrome b5 Reductase/NADH System. Biochemistry 56:3993-4004
Amdahl, Matthew B; DeMartino, Anthony W; Tejero, Jesús et al. (2017) Cytoglobin at the Crossroads of Vascular Remodeling. Arterioscler Thromb Vasc Biol 37:1803-1805
Koch, Carl D; Gladwin, Mark T; Freeman, Bruce A et al. (2017) Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health. Free Radic Biol Med 105:48-67
Lee, Janet S; Kim-Shapiro, Daniel B (2017) Stored blood: how old is too old? J Clin Invest 127:100-102

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