All ETDs from UAB

Advisory Committee Chair

Rakesh P Patel

Advisory Committee Members

Shannon Bailey

Victor Darley-Usmar

Jeannette Doeller

Sadis Matalon

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The recent discovery that red blood cells might mediate hypoxic blood flow together with accumulating evidence that suggests a role for the modulation of vascular inflammation has reshaped the way we think about the function of these cells. In this thesis we investigate the mechanisms that regulate these newly appreciated functions and focus on i) the ability of red cells to couple oxygen sensing with nitrite reduction and nitric oxide formation and ii) the role of the beta93cys, a conserved residue amongst mammalian hemoglobins and whose function remains unclear. Data will be presented that demonstrate that nitrite reduction to nitric oxide by red blood cells is regulated by an oxygen-sensitive mechanism that controls nitrite transport through the cell membrane. Additionally, evidence will be provided showing that the nitrite reductase activity of heme proteins can be harnessed for the development of clinically viable hemoglobin based blood substitutes. More specifically we show that coadministration of sodium nitrite prevents the hypertensive response commonly observed after transfusion with a hemoglobin-based blood substitute. Finally, data will be presented that suggest that the beta93cys residue modulates acute vascular and pulmonary inflammation via reactions with reactive oxygen and chlorine species which in turn may protect against vascular and end organ injury in acute inflammation

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