Studies on actin polymerisation and deformability in polymorphonuclear cells and monocytes
Cardiff Metropolitan University
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Leukocytes become activated in response to hazards such as bacteria, viruses and particulates, and this activation results in reduced blood flow in disease states. This activation is associated with assembly of the cytoskeleton, including actin polymerisation, in preparation for extravasation and phagocytosis. Cytoskeletal organisation is a major factor determining leukocyte deformability and one of the major causes of leukocyte trapping and reduced microcirculatory flow in disease. The aim of this thesis is to investigate the alteration in F-actin content and its association with activation and leukocyte deformability. All measurements were performed on whole blood samples of humans and Male Sprague Dawley rats using a simplified method to quantify and visualise F-actin content in leukocytes based on flow cytometric analysis and fluorescence microscopy. The Cardiff Filtrometer was used to study the association between leukocyte transit times, pore-blockers and F-actin content. Full blood counts, F-actin content and plasma viscosity were measured in rat blood after animal instillation of PM10. In addition, in vitro measurements were performed to investigate the effects of therapeutic agents that bind peroxisome proliferator-activated receptor (PPAR y) on the F-actin content of leukocytes. The results showed an increase in leukocyte F-actin after treating blood with either Phorbol 12-Myristate 13-Acetate (PMA) or Formyl-Methionyl-Leucyl-Phenylalanine (fMLP) and this effect was inhibited by the addition of CTB. These measurements were performed simultaneously with the filtration method, and correlated significantly (r=0.217 with p=0.029) between the F-actin content of PMNs and leukocyte transit time. Another significant correlation (r=0.798 with p<0.001) was also observed between the F-actin content of PMNs and monocytes (r=0.763 with p<0.001) and the number of pore blockers. There was an apparent increase in leukocyte F-actin content in rats instilled with PM10, although these results were not statistically significant. The treatment of human blood with PPAR y agonists resulted in a rapid decrease in the F-actin content of both PMNs and monocytes, which may result from the inhibition of early signalling cascades involved in actin polymerisation.
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