Histamine as a Potential Initiator of Sickle Pain crisis by Mediation of Sickle Erythrocyte Adherence in a Shear-Dependent Manner

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Wagner, Matthew Christian
Wick, Timothy M.
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The genetic disorder sickle cell anemia causes hemolytic anemia and sickle pain crisis, episodes of microvascular occlusion resulting in painful ischemic tissue damage. Pain crisis is thought to occur when sickle erythrocytes adhere in the post-capillary venule, partially occluding the vessel. The resulting slowed blood flow causes more extensive cell adherence and entrapment of rigid, deoxygenated erythrocytes until the vessel is entirely occluded. It was hypothesized that the inflammatory mediators histamine and tumor necrosis factor-, factors known to cause endothelial expression of adhesive ligands, might significantly increase sickle erythrocyte adhesion, and thus be capable of initiating sickle pain crisis. It was also hypothesized that the perfusion shear stress environment of the endothelium, known to be oscillatory and reduced in sickle cell patients, was a significant mediating factor of sickle cell adhesion. An in-vitro flow chamber using cultured endothelial cells and erythrocytes from blood samples of sickle cell anemic patients was used to quantify sickle erythrocyte adherence to stimulated and unstimulated endothelial cells under shear stresses from 1.0 to 0.1 dyne/cm2. Results showed that both endothelial stimulation and reduction of the perfusion shear stress increased sickle erythrocyte adherence. In combination, the use of inflammatory stimulation with reduced shear stress resulted in further increased adhesion, but only when above the range of 0.1 V 0.2 or 0.4 dyne/cm2, depending on the inflammatory mediator. Adhesion below this level of shear is not significantly increased by endothelial stimulation. The mechanism by which histamine mediates adhesion was investigated, and found to involve the endothelial H2 and H4 receptors and expression of the P-selectin ligand. These data suggest that irregular flow, typical of sickle microvasculature, may act in conjunction with the pro-inflammatory state of sickle vasculature and the histaminergic nature of some pain treatments to initiate or propagate sickle vaso-occlusion. Findings concerning histamine, tumor necrosis factor-alpha, and shear stress effects on adherence are discussed in relation to their possible applicability to patient health, future studies are outlined to confirm the relation of in vitro data to in vivo patient condition, and proposals are made for applying these methodologies to other potential mediators of sickle erythrocyte adhesion.
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