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Ren, Hongmei (2007) Membrane fatty acids and antioxidants of patients with sickle cell disease: implications for vaso-occlusion and manifestations. Doctoral thesis, London Metropolitan University.
Sickle cell disease (SCD) is the most common hereditary blood disorder, which is characterised by recurrent vascular occlusion and widespread organ damage. The organs that are often affected include spleen, brain, kidneys, lungs and bones. The vaso-occlusive events of SCD were thought to be due to the blockage of small blood vessels by deformed (sickled) red cells. However, the frequency of vaso-occlusive crises and the clinical severity of the disease do not correlate with the number of sickled red cells. In contrast, they do correlate with adhesion of red cells to vascular endothelium, blood cell aggregation and inflammation. Adhesion and aggregation of blood cells, and inflammation are strongly influenced by membrane fatty acids, specifically long chain polyunsaturated fatty acids (LCPUFA). Hence, there may be cause and effect relationship between reduced levels of blood cell membrane LCPUFA and enhanced vaso-occlusion. This thesis reports findings of studies conducted to investigate: a) if homozygous sickle cell anaemia (HbSS) has adverse effect on plasma and/or blood cell membrane fatty acids; b) the extent of modulation of membrane fatty acids by background diets and antioxidants in HbSS patients; c) if compound heterozygous sickle cell haemoglobin C (HbSC) disease, which has similar but less severe clinical manifestations compared with HbSS, has any effect on plasma and/or blood cell membrane fatty acids. To answer these questions, patients with HbSS and HbSC, and their respective HbAA healthy controls were enrolled from Nigeria and the United Kingdom. These studies revealed that steady state HbSS patients, regardless of their geographical origin, had abnormal plasma, red cell, platelet and mononuclear cell fatty acid composition. This abnormality was characterised, primarily, by higher levels of arachidonic (20:4n-6, AA) and adrenic (22:4n-6) acids, and lower eicosapentaenoic (20:Sn-3, EPA), docosahexaenoic (22:6n-3, DHA) acids and total n-3 metabolites in choline (CPG) and ethanolamine (EPG) phosphoglycerides of red cells and platelets. Similarly, the total phospholipids of mononuclear cells had increased AA, and decreased DHA and n-3 metabolites. The HbSC patients, who have the milder form of SCD, consistent with the clinical severity of the disease, had similar but less pronounced plasma and red cell fatty acid abnormality compared with their HbSS counterparts. The levels of haemoglobin were positively correlated with red cell membrane EPA, DHA and total n-3 fatty acids in the Nigerian HbSS patients. This suggests that a higher level of membrane n-3 LCPUFA confers protection against haemolysis in SCD. Such a relationship was not apparent in the British patients, most likely due to low sample size. The levels of LA, EPA and DHA in CPG and EPG of red cells were lower in both groups of patients with SCD compared with their respective healthy controls. However, in comparison with the Nigerian patients, LA was significantly higher in red cell CPG and EPG of the British patients reflecting a high intake of the fatty acid from vegetable seed oils. In contrast, consistent with the high fish intake in Enugu and the coastal regions of Nigeria, the Nigerian patients had higher levels of EPA and DHA in red cell CPG and EPG compared with their British counterparts. These results indicate that membrane fatty acids in patients with sickle cell disease are responsive to dietary manipulation. The concentrations of the fat-soluble antioxidant vitamins (a-tocopherol and B-carotene), and the activity of the red cell antioxidant enzymes (Cu/Zn-superoxide dismutase and Se-glutathione peroxidase) were lower in the HbSS patients of both countries. Likewise, the HbSC patients, had reduced but less pronounced levels of the vitamins and antioxidant enzyme activities. The compromised antioxidant status in the patients is consistent with the enhanced oxidative stress in sickle cell patients reported in previous studies. The observed abnormalities of n-6 and n-3 LCPUFA of red cells, platelets and mononuclear cells in the patients with sickle cell disease could be due to a metabolic perturbation induced by the disease and/or the enhanced peroxidation of the highly unsaturated, labile, n-3 LCPUFA caused by oxidative overload. Regardless of the causations, such membrane n-6 and n-3 LCPUFA abnormalities would have profound adverse effects on cell adhesion, aggregation, inflammation, and consequently physiological functions. There is a very urgent need to investigate if supplementations with n-3 LCPUFA and antioxidants ameliorate vaso-occlusions in sickle cell patients.
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