The Effect of Antioxidants on the Properties of Red Blood Cells From Patients With Sickle Cell Anemia.

Halima Al Balushi,David Rees,John Brewin,Anke Hannemann,John Stanley Gibson

doi:10.3389/fphys.2019.00976

Abstract

Oxidative damage to red blood cells (RBCs) may contribute to pathogenesis of sickle cell anemia. Reducing the deleterious effects of oxidants by exposing RBCs to a number of antioxidants has been shown to have protective effects against lipid and protein peroxidation. We hypothesize that antioxidants may also have beneficial effects on the abnormal membrane permeability of sickle cells. Increased cation permeability of these cells encourages HbS polymerization by causing RBC dehydration and also leads to externalization of the prothrombotic aminophospholipid phosphatidylserine (PS). Three antioxidants with different mechanisms of action were investigated – dithiothreitol, N-acetylcysteine, and quercetin. All three were found to inhibit the main cation pathways responsible for dehydration – the deoxygenation-induced cation conductance (or Psickle), the Ca2+-activated K+ channel (or Gardos channel), and the K+-Cl− cotransporter. They also reduced Ca2+-induced PS exposure and hemolysis. Findings provide evidence for additional beneficial actions of antioxidants in maintenance of rheology and reducing vascular adhesion and further inform the rationale for their clinical use.

Highlights

Antioxidants are used in the treatment of many disorders notably neoplasia and including sickle cell anemia (SCA), in which a phase 3 clinical trial of L-glutamine has recently been carried out (Niihara et al, 2018)
At full deoxygenation, sickling was markedly reduced from 75 ± 3 to 50 ± 4% (Figure 1A, p < 0.01), while inhibition was still present though at smaller magnitudes at 30 and 100 mmHg O2
There was a significant correlation between Psickle activity and sickling in red blood cells (RBCs) treated with quercetin (Figure 1C), consistent with the sickling shape change activating this conductance

Summary

Introduction

Antioxidants are used in the treatment of many disorders notably neoplasia and including sickle cell anemia (SCA), in which a phase 3 clinical trial of L-glutamine has recently been carried out (Niihara et al, 2018). Any effect on red blood cell (RBC) membrane permeability, has been largely ignored and is the subject of this report. RBCs from patients with sickle cell anemia (of HbSS genotype; SCA) contain the abnormal hemoglobin (Hb) HbS. The resultant long, rigid polymers of HbS initiate a concatenation of events resulting in the clinical signs observed in SCA patients. These fall largely into two groups: a chronic hemolytic anemia and acute episodes of vaso-occlusive ischemia. Complications include pain, acute chest syndrome, stroke, nephropathy, osteonecrosis, leg ulcers, and reduced lifespan, though both the frequency

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Conclusion