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    • These data suggest that the dehydration of the SSRBCs induce

    2021-10-15

    These data suggest that the dehydration of the SSRBCs induced by RANTES might result of an activation of the Gardos channel mediated by the chemokine receptor DARC. However, direct evidence of Gardos channel activation by chemokines in Duffy-positive SSRBCs leading to cell dehydration has not been evaluated. It is not known whether CXC and CC chemokines can modulate the Gardos channel activity of SSRBCs in vivo. IL-8 has been described to play a role in the initiation or propagation of vaso-occlusive and acute chest syndromes in patients with SCA [14], [15], [16]. The present study, conducted with Duffy-positive and Duffy-negative SCA patients, was undertaken to evaluate the effect of both CXC (IL-8) and CC chemokines (RANTES) on the Gardos channel activity in SSRBCs, under physiological conditions by the determination of charybdotoxin-sensitive K+ loss, in the absence of the Ca2+ ionophore A23187 in a medium containing 2mM Ca2+.
    Materials and methods
    Results
    Discussion The main findings of this study are the following: (1) the percentage of SB 203580 hydrochloride with density higher than 1.120, generally corresponding to irreversibly sickled cells, is 17 times more important in the Duffy-positive group of patients; (2) Duffy-positive SSRBCS incubated under oxygenated conditions exhibit a Gardos channel activation; and (3) the chemokines IL-8 and RANTES elicit a stimulation of the deoxygenation-stimulated K+ loss via the Gardos channel in the Duffy-positive SSRBCs but not in the Duffy-negative SSRBCs. The generation of dense cells and irreversibly sickled cells, which contribute to the physiopathology of the sickling syndromes, results of the loss of solute and osmotically obliged water through specific pathways. Schwartz et al. [21] defined intermediate-density (ID) and high-density (HD) fractions of erythrocytes as 1.090–1.114g/ml and >1.114g/ml and showed that the Gardos Channel is largely responsible for HD formation. Other studies have identified the Gardos channel as the predominant way for dense cell formation after the treatment of the RBCs with oxidants [11], [22], [23]. The higher percentage of RBCs with a density >1.120 in the Duffy-positive group might result from an in vivo Gardos channel activation of the SSRBCs in this group by the repetitive cycles of deoxygenation. The Gardos channel is regulated mainly by [Ca2+]i that is dependent on the level of passive Ca2+ entry and the activity of the plasma membrane Ca2+-ATPase. Its Ca2+ sensitivity can increase in response to oxidative damage [11], RBC protein phosphorylation [24], or exposure to cytokines [10]. Gardos channel activation in SSRBCs incubated in physiological saline medium (without Ca2+ ionophore) under oxygenated conditions either has not been detected when K+ loss was followed by the measure of K+ by flame emission spectroscopy, as in the present study [25], or has been detected at very low levels when K+ loss is followed by the use of 86Rb+ as a congener for K+ [11]. In the present study, we have detected a ChTX-sensitive K+ loss in the Duffy-positive but not in the Duffy-negative SSRBCs at the end of 120min of incubation under oxygenated conditions. These data suggest that the Gardos channel activity detected in the oxygenated Duffy-positive SSRBCs, and mainly in the cells that have been stored for a longer time before processing, might reflect the occurrence of oxidation processes and a greater susceptibility of the Duffy-positive SSRBCs than the Duffy-negative SSRBCs to cellular oxidations. IL-8 and RANTES, which did not affect the Gardos channel activity measured in the Duffy-positive SSRBCs under oxygenated conditions, allowed a stimulation of the deoxygenated-stimulated and ChTX-sensitive K+ loss. The Gardos channel activity under deoxygenated conditions may result in the additive stimulatory effect by oxidation of the RBC membrane and Psickle. Muzyamba et al. [11] showed that the increased Gardos activity induced by 1-chloro-2,4-dinitrobenzene, which causes oxidative damage, was not associated with an increased Ca2+ influx but rather by inhibition of the plasma membrane Ca2+-ATPase and by an increased in the Ca2+ sensitivity of the channel. The current results are consistent with an effect of the chemokines on the Gardos channel activation mediated by Ca2+ influx through the deoxygenation-induced pathway.