The possibility that polymorphonuclear neutrophils (PMN) or monocytes (MN) initiate or promote vascular occlusion in sickle cell disease (SCD) has not been explored. PMN are very sensitive to inflammatory mediators and are easily transformed to sticky, rigid cells which occlude small vessels and as such, could initiate vascular occlusion in SCD. Preliminary measurements of PMN deformability and integrin receptor expression in SCD suggest PMN are very rigid and have increased adhesion receptors. This project explores the hypotheses that a) the degree of activation of PMN/MN correlates with frequency and severity of vaso-occlusive complications of SCD and b) soluble inflammatory mediators or contact of PMN/MN with sickle red cells (SRBC) cause activation of PMN/MN making them rigid and hyper-adherent and thus likely to occlude small vessels. The state of phagocyte activation in patients with SCD will be determined by measuring changes in PMN/MN """"""""activation parameters"""""""" (adhesion receptors CD11b and Leu8, F-actin content, and PMN/MN deformability) and will be related to the incidence and severity of vaso-occlusive complications of SCD, beta-globin gene haplotype, or treatment with hydroxyurea or ticlopidine as outlined in other projects in this program. Patients will be followed serially to see if changes in PMN/MN activation precede development of crisis. The ability of PMN from patients with SCD to ingest bacteria will be related to propensity to infection and severity and frequency of sickle vaso occlusive complications as monitored in Projects 1 and 5 (""""""""haplotype"""""""" and """"""""stroke"""""""" projects). The mechanism by which SCD plasma activates PMN/MN will be studied in vitro by measuring the """"""""activation parameters"""""""" after exposing normal PMN/MN to SCD plasma or supernatants of MN exposed to SRBC. Putative activating agents tumor necrosis factor(TNF), interleukin-1 (II-1) and prostaglandin metabolites will be directly measured in supernatants and plasma. We will attempt to block the plasma-induced activation due to TNF or IL-1 (known to be increased in SCD) with soluble recombinant IL-1 or TNF receptor. The mechanism by which PMN/MN recognize SRBC, resulting in PMN/MN activation, will be studied. RBC or SRBC will be exposed to resting and cytokine primed PMN/MN and changes in the """"""""activation parameters"""""""" will be monitored. PMN/MN become activated when they phagocytose or adhere to SRBC. We will determine the mechanism of attachment and phagocytosis of SRBC by PMN/MN by blocking putative recognition receptors with anti (CD11b antibody, RGD peptide, phosphatidyl serine or antibodies to the putative SRBC integrin receptor (Project 2) and determining if phagocytosis or adhesion of SRBC to PMN/MN is blocked.
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