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We have shown that the adherence of sickle red cells (RBCs) to macroendothelium (MacroECs) is increased if the ECs are previously subjected to short term hypoxia. Inhibition of the EC lipoxygenase (LO) pathway totally abolished hypoxia mediated RBC-EC adherence. We will ascertain whether similar changes occur in capillary ECs and the specific arachidonic and/or linoleic acid LO products (mono- and di-HETEs, LTs and HODES) involved. We will further ascertain whether hypoxia induced RBC-EC adherence is mediated via participation of adhesive receptors and the nature of these receptors (especially since the reticulocyte appears involved in this interaction). The effects of LO metabolites on FC adhesive receptor expression will also be assessed. Our clinical studies will focus on patients with sickle cell disease (SCD) with either acute or chronic hypoxia. Plasma and urine levels of the putative LO metabolites and RBC-EC adhesion will be evaluated in classic Acute Chest Syndrome (ACS) and in incipient ACS daily during the patient's hospitalization. Our hypothesis is that levels of the LO metabolites that enhance adhesion and that adversely effect microcirculatory tone and airway contractility will be elevated during ACS and acute hypoxia, or may even predate worsening hypoxia' and thus perpetuate ACS or predict its evolution. Finally, SCD patients, identified in the concurrent pulmonary project to exhibit awake and/or sleep hypoxemia, will have steady state plasma and urinary levels of the putative LO products and adhesion assessed. We predict that levels of the adhesionogenic metabolites will be elevated in this patient subgroup as a response to chronic hypoxia when compared to children with SCD who are normoxic. Other appropriate controls including normal children and children with obstructive apnoea without hemoglobinopathy will be studied. Eicosanoid levels will be reassessed post therapeutic intervention (medical or surgical) to treat the hypoxia. Thus causal relationships (if present) between levels of the putative LO metabolites and hypoxia both acute or chronic will be ascertained. While no therapeutic interventions related to eicosanoid metabolism are proposed, the use of cycloxygenase and/or thromboxane (Tx) synthase inhibitors has proven of benefit in conditions where TXA2 is the main putative metabolite causing acute adverse pulmonary pertubations. Thus relevant therapeutic implications may result as a consequence of this proposal which seeks to define a relationship between eicosanoids and hypoxia in patients with SCD both in the laboratory and clinical setting.
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