Many studies now support the concept that the pathophysiologic of sickle cell disease is a result of the tendency of hemoglobin S to polymerize. Furthermore, the diverse clinical manifestations of the illness, that can affect virtually every organ in the body are, for the most part, explainable by the impaired rheologic behavior of red cell sin which such polymer is present. Evidence now also indicates that SS RBC possess a variety of defects in cell membrane structure and function. While the causes of these abnormalities areas yet uncertain, the end results include an inability of the cells to maintain a normal potassium content, an impairment of cell volume homeostasis, and cell dehydration. Since the polymerization reaction is very sensitive to cell hemoglobin S concentration, these membrane defects, and the associated reduction in cell ion and water content, accelerate the polymerization process, and thereby exacerbate the manifestations of sickle cell disease. The studies to be described will attempt to identify the mechanisms by which euhydrated, reversibly sickled cells become transformed into dehydrated, irreversibly sickled cells. The hypotheses to be tested are: a) the abnormalities in membrane function are acquired, their development in some manner being related to the intracellular polymerization of hemoglobin S and the accompanying cell sickling; and b) shearing forces such as those experienced in the microvasculature act in a synergistic fashion with deoxygenation-induced sickling, thus accentuating further the permeability changes resulting from these acquired abnormalities in cell membrane function. The experiments proposed here will employ PO2 scan ektacytometry, coneplate viscometry, and NMR spectroscopy to study the physiologic effects on sickle RBC of deoxygenation- induced sickling and shearing forces, alone and in combination. In addition, attempts will be made to identify therapeutic modalities that will prevent the changes in cell composition brought on by these two variables.
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