The overall goal of this project is to explore how activation of leukocytes in patients with sickle cell disease (SCD) promotes vascular damage and crisis. The molecular defect in SCD, a point mutation of the beta globin gene, has been known for years and its biophysical consequences and role in sickle vascular diseases have been extensively explored. However, the substantial variation in clinical presentation, morbidity and mortality in SCD patients have been extensively explored. However, the substantial variation in clinical presentation, morbidity and mortality in SCD patients remains largely unexplained and suggests that factors other than the defective hemoglobin can affect the course of this disease. We previously proposed that the inflammatory cells, i.e. polymorphonuclear neutrophils (PMN), monocytes (MN), macrophages (MP) and platelets (PLT) and the inflammatory mediators they produce participate in the genesis of SCD vasoocclusion. We showed that PMN from SCD patients (SCD-PMN) are very rigid and have increased adhesion receptors, suggesting activation. We also showed that sickle red blood cells (SRBC) specifically adhere to normal PMN through IgG- and RGD-mediated mechanisms resulting in MN activation and production of reactive oxygen species. Our preliminary data indicate that SCD-PMN exhibit phosphatidylserine asymmetry, a process associated with apoptosis and known to play a role in recognition of apoptotic cells by MP. We also showed that PS-mediated binding to MP induces the subsequent production of pro-inflammatory cytokines. These data are in support for a role for leukocytes in the initiation of vascular occlusion and in the pathogenesis of SCD. We hypothesize that the degree of activation of leukocytes correlates with the frequency and severity of vasoocclusive complications in SCD. We further hypothesize that specific interactions between SRBC and leukocytes result in the production of inflammatory products and/or changes in the MN and MN biophysical properties that could initiate and promote vasoocclusive crisis in SCD patients. To test these hypothesis, we will: 1) Determine the changes in the plasma levels of inflammatory mediators or cellular (PMN/MN/MP/PLT) markers of activation that implicate leukocytes in the genesis of vascoocclusion from SCD patients and correlate them with clinical severity of disease. We will determine if the defects are intrinsic to SCD leukocytes or secondary to environmental factors; 2) Determine the mechanisms which mediate the static attachment of SRBC to PMN/MN/MP and the result in subsequent production of inflammatory mediators; 3) Determine the signal transduction mechanisms by which PMN/MN are activated by SRBC; 4) Determine the mechanisms by which SRBC attach to monolayers of PMN/MN/MP under flow conditions and activate the PMN/MN/MP forming the monolayer. These studies will demonstrate the role and mechanism of leukocyte activation and increased inflammatory tone in the initiation and promotion of vasoocclusive crisis in sickle cell disease.
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