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Title: The role of endothelial adhesins in leukocyte adhesion in response to pharmaceutical agents that induce pulmonary fibrosis
Author: Williamson, James Denis
ISNI:       0000 0004 5914 6805
Awarding Body: University of Hull and the University of York
Current Institution: University of Hull
Date of Award: 2015
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Bleomycin (BLM) is an antineoplastic agent known to cause pulmonary fibrosis as a side-effect, and is often used to model fibrotic disease in rodents. Although human BLM-induced pulmonary fibrosis (BPF) results from intravenous BLM delivery, rodent modelling today primarily uses the intratracheal delivery method. However, BPF following both dosing routes is characterised by inflammatory cell influx into the lung. Though it is thought that intratracheal dosing causes intrapulmonary injury, cytokine release, and resultant immune cell recruitment, the mechanism by which intravenous dosing causes immune cell influx is less clear. Endothelial cells are critically involved in immune cell extravasation to the site of injury, through adhesion molecule expression and cytokine release. This work assessed whether BLM induces endothelial adhesion molecule expression and cytokine release. It was found that the treatment of HUVECs and PMVECs with pharmacologically-relevant concentrations of BLM resulted in increased ICAM-1, VCAM-1, and (in HUVECs) E-selectin expression, and increased MCP-1 and IL-8 release. Endothelin-1 release was decreased by treatment. These alterations were regulated at a mRNA transcriptional level. Endothelial cell treatment with BLM also supported increased neutrophil tethering and adhesion to endothelial monolayers, although this appeared unrelated to increased ICAM-1 or E-selectin expression. This work reports the novel finding that pharmacologically-relevant concentrations of BLM increase adhesion molecule expression in both HUVECs and PMVECs, and compares the expression of adhesion molecules and cytokines in these cell types in response to BLM. This thesis also reports the unique discovery that BLM treatment increases leukocyte adhesion to endothelial monolayers under flow in vitro. Finally, the finding that endothelial adhesion molecule expression and cytokine release is increased in response to treatment with etoposide, another agent which causes lung fibrosis, is presented. This work suggests a potential mechanism which may contribute to the development of human BPF via immune cell recruitment to the lung. NB: The hard copy which contains a CD-ROM of videos is available for consultation in the Brynmor Jones Library.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine