Saharay, Mrinal; (1998) The role of leucocytes in the pathogenesis of skin damage due to chronic venous disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Leucocyte trapping in the microcirculation has been suggested as the cause of skin damage seen in chronic venous disease. In this thesis the effect of experimental venous hypertension on circulating leucocytes and the vascular endothelium was investigated. Normal volunteers and patients with chronic venous disease both with and without skin damage were studied. Activation markers for neutrophils and monocytes were measured, before and after exposure to experimental venous hypertension. Markers of endothelial activation were also investigated. Finally, leucocyte migration from the circulation into the tissues, and the role of cytokines were explored. Neutrophil and monocyte activation was investigated by measuring the cell surface expression of the integrin CD11b/CD18 and the selectin CD62L by a whole blood assay using fluorescent-labelled monoclonal antibodies. CD62L, which is shed by leucocytes upon activation, was also measured in plasma by a commercially available ELISA. Endothelial adhesion molecules VCAM-1, ICAM-1, ELAM-1 and vWf which act as counter ligands for adhesion molecules expressed by leucocytes and are shed into the plasma were measured by commercially available ELISAs. Neutrophil and monocyte activation occurred in control subjects and patients following experimental venous hypertension. Leucocyte-endothelial adhesion was greater in patients than controls. In-vivo leucocyte migration in volunteers subjected to short term venous hypertension was investigated using the 'Skin Window Technique'. Superficial dermal skin abrasions were made and emigrating leucocytes collected on micropore membranes placed over the abrasions. These were stained and examined by light microscopy to determine the cell types which had emigrated and the distance travelled by the cells within the membrane. Leucocyte migration in the tissue decreased following experimental venous hypertension. The cytokines IL-6 and TNF-α were measured by an ELISA and found to be higher following venous hypertension. These studies show that short-term, experimental, venous hypertension causes leucocyte and endothelial activation and adhesion, which is known to precede extra-vascular migration. Following emigration leucocyte locomotion decreases which may lead to localised accumulation of activated leucocytes releasing toxic metabolites and free radicals resulting in tissue damage.

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