Packed red blood cell (PRBC) transfusions are associated with increased morbidity and mortality in critically patients. The etiology underlying this association remains uncertain, as a clinical benefit has not been convincingly demonstrated by randomized controlled trials of leukoreduction. Others have postulated that the non-leukocyte component of red cell concentrates modulates the systemic inflammatory response, although data to support a plausible mechanism has been lacking. The Duffy antigen, expressed on erythrocytes and venular endothelium, binds multiple chemokines and is one potential modifier of local and systemic inflammatory responses. We have recently shown that endothelial Duffy antigen binds and sequesters soluble chemokines to dampen local tissue inflammation. We have also shown that erythrocyte Duffy functions as a chemokine reservoir, reducing soluble chemokine concentrations in local tissue vascular beds but increasing systemic chemokine bioavailability, thereby facilitating neutrophil influx into the airspaces in an LPS model of lung inflammation. The long-term objectives are to better understand how Duffy contributes to the formation of chemotactic gradients, specifically addressing the process of selective chemokine movement from the lungs to the vascular compartment, and determining whether erythrocyte administration can modulate this process. We will determine if Duffy mediates selective chemokine mobilization from the airspaces to the vascular compartment, and whether this process involves Duffy-ligand internalization through a caveolae-mediated pathway in endothelial cells. We will also determine whether augmenting Duffy binding sites through PRBC transfusions alters systemic chemokine concentrations and neutrophilic influx into inflamed lungs. We will use a variety of in vitro and in vivo approaches including Duffy endothelial transfectants and caveolin-1-/- cells to study the mechanism of internalization, Duffy knockout (dfy-/-) mice to study chemokine mobilization in vivo, and chimeric mice using irradiated dfy-/- and dfy+/+ mice reconstituted with dfy-/- or dfy+/+ marrow to define the relative contribution of endothelial and erythrocyte Duffy in vivo. Knowledge derived from these studies may elucidate one mechanism of modifying local tissue and systemic inflammatory responses and provide new insight to a common issue in the critically ill.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086884-04
Application #
7805457
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Harabin, Andrea L
Project Start
2007-07-18
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$371,065
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
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