All ETDs from UAB

Advisory Committee Chair

Rakesh P Patel

Advisory Committee Members

Scott Ballinger

Jeff Kerby

Jack Lancaster

Marisa Marques

Roger White

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Transfusion with red blood cells (RBC) remains a frontline therapy in critically ill patients. Recent studies have documented an association between storage duration and an increased incidence of transfusion-related toxicities. This transfusion-related toxicity is characterized by both a pro-inflammatory state and a microcirculatory dysfunction and is associated with changes that occur to the RBC and its media during storage referred to as the storage lesion. These changes that occur to the RBC include an increase in cell-free hemoglobin, heme, free iron, microparticles, as well as changes to the RBC itself. This thesis explores how these elements could contribute to transfusion-related toxicity. Erythrocytic hemoglobin can rapidly scavenge nitric oxide (NO), thereby inhibiting NO signaling leading to inflammation and microcirculatory dysfunction. We show that storage-related changes in RBC lead to increased NO-scavenging kinetics with RBC stored for 42 days compared to those freshly isolated; an affect that translated to a greater inhibition of NO-dependent vasodilation. We also have developed a mouse model of storage lesion that involves a first hit of trauma/hemorrhage followed by a second hit caused by transfusion with stored blood. Using this model we show that acute lung injury can be attenuated and survival increased by i) washing RBC to remove storage media, ii) nitrite administration, and iii) inhibition of the TLR4 receptor by TAK-242.

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