Autoxidation, dehydration, and adhesivity may be related abnormalities of sickle erythrocytes

The sickle gene has remarkably pleiotropic effects. In an attempt to understand the complex pathobiology of sickle disease, we have searched for potential relationships between various cellular abnormalities. In the present studies, we treated normal erythrocytes (RBCs) with phenazine methosulfate to stimulate intracellular generation of superoxide and thereby stimulate the excessive autoxidation characteristic of sickle RBCs. In response, RBCs show a dose-dependent increase in adherence to endothelium, easily achieving the degree of abnormal adherence typical of unmanipulated sickle RBCs. This is mediated by adverse effects of oxidant on cellular hydration, as evidenced by amelioration of abnormal adhesivity if the drug's dehydrating effect is inhibited. Consistent with potential relevance of this to sickle pathobiology, the abnormal endothelial adherence of sickle RBCs can be worsened or improved by dehydrating or hydrating these cells, respectively. These data suggest an intimate relationship between three abnormalities of sickle RBCs previously thought to be unrelated (autoxidation, dehydration, and adhesivity). Although multiple mechanisms may contribute to abnormal cell-cell interactions in sickle disease, the potentiation of sickle RBC adhesivity by cellular dehydration may help explain why clinical dehydration has been identified as a precipitant of vasocclusive crisis. Insofar as abnormal adhesivity participates in the sickle vasocclusive process, these data provide further rationale for attempting to manipulate RBC hydration as a therapeutic maneuver in this disease.