Hartley, Andrew Philip; (1991) Oxidative stress in sickle erythrocytes: membrane-associated iron-compounds and approaches to the suppression of cell damage. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In these studies iron-containing compounds associated with the erythrocyte membrane in the haemoglobinopathy sickle cell anaemia have been investigated with respect to their nature, catalytic activity and location. It has previously been suggested that membrane-associated iron catalyses processes leading to oxidative membrane damage in these erythrocytes. Additionally, the potential contribution of membrane oxidation in sickle erythrocytes to the pathology of the disease has been examined in the present studies. Non-haem iron was detected in sickle, but not normal, erythrocyte membrane preparations. Further investigation indicated that these iron-species are associated with the cytoskeletal protein component of the erythrocyte membrane and that they are able to catalyse the propagation of lipid peroxidation. The possibility that oxidative membrane damage contributes to the characteristic morphological degeneration of sickle erythrocytes and thereby the pathology of the disease has been assessed using an incubation system which mimics the repeated deoxygenation and oxygenation experienced by erythrocytes in the circulation and reproduces the physiological degeneration of sickle erythrocytes. The results indicate that oxidative damage is not an important factor in the formation of irreversibly sickled cells or cell dehydration, factors believed to contribute to vaso- occlusion. However, a positive correlation was found between erythrocyte membrane lipid peroxidation and the frequency of vaso-occlusive crises which is discussed in terms of other processes potentially contributing to vaso-occlusion. Using the same incubation system it has been demonstrated that the hydroxypyridinone iron chelator CP094 can enter intact sickle erythrocytes, chelate the non-haem iron and suppress lipid peroxidation. Desferrioxamine was less effective, consistent with a slow rate of entry into erythrocytes. Additionally, the ability of desferrioxamine to scavenge radicals by donation of a hydrogen atom from a hydroxamate group has been demonstrated. Thus antioxidant effects of desferrioxamine must be interpreted with respect to both iron chelation and radical scavenging.

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