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Title: Monocyte and fibrocyte characterisation in asthma
Author: Al-Reshoudi, Reem Hamoud
ISNI:       0000 0004 6423 2943
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2017
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Monocytes and their subsets play an important role in immune and inflammatory diseases. In this study the focus was on their role of driving pathogenesis in asthmatic patients. The hypothesis was that although monocytes have not been identified as key players in atopic disease they are likely to be pro-inflammatory, be readily recruited to tissue and have a major role in the exacerbation of disease. This may relate to the prevailing pro-inflammatory microenvironment. Chemokines such as CCL2 and CX3CL1 are involved in monocyte recruitment and survival respectively in the inflamed tissues. Three subsets of monocytes namely CD14++CD16-, CD14++CD16+ and CD14+CD16++ monocytes are known to express chemokine receptors. Alterations if any in the numbers or in the molecular inflammatory markers of these three monocyte subsets with contrasting potential of modulating inflammatory responses in the peripheral blood may provide some insight in the disease process. It is also believed that circulating fibrocytes in allergic asthma are the cause of fibrosis in chronically inflamed pulmonary tissues resulting in refractory asthma. Fibrocytes, also derived from the bone marrow, produce connective tissue components such a collagen-1 and can adopt a mesenchymal phenotype and contribute to granulomas, scar tissue and tissue remodeling. They appear to play an important role in chronic and refractory asthma but have also been found in lungs of patients with mild asthma indicating that they may play an as yet undefined role in the development of inflammation. Fibrocytes also express chemokine receptors and their recruitment in tissues may also depend upon chemokines. Using six-color flow-cytometry phenotypic analysis of human blood monocyte and fibrocyte populations from asthma patients was performed along with the isolation of mRNA from CD14+ monocytes for assessment of inflammatory markers expression and the data was compared with the normal healthy individuals. Based on the findings of gene expression an attempt was made to demonstrate the effect of routine treatment used by our patients on gene expression of selectively isolated monocytes from healthy individuals. Finally serum levels of chemokines between patients and normal healthy controls were also determined. XXI From the flow-cytometry analysis we demonstrated a significant increase in both CD45-positive monocytes and circulating fibrocytes in severe asthmatic patients. While CCR2 percentage was significantly increased, the CX3CR1 percentage was significantly decreased in the intermediate and non-classical monocyte subsets in both mild and moderate patients, however these changes were only observed in the non-classical monocytes in severe patients. In the gene expression the proinflammatory receptors CCR2, CCR5, CX3CR1, IL-17RA, and cytokine inhibitor SOCS3 in monocytes were all significantly reduced in the severe asthma patients. While CCR1 and CD36 were significantly decreased in mild and moderate asthmatic patients. No significant change in serum pro-inflammatory cytokines were detected although IL-5 was significantly increased in moderate and severe asthmatic patients. Analysis of monocyte gene expression in asthma by other groups although not highlighting a specific gene did indicate that inflammatory and TNF pathways might be involved. In conclusion there was a tendency toward more inflammatory monocytes in our asthma patients, however this was not clearly reflected in the patients serum profile given that inflamatory monocytes make up only a small percentage of the leukocytes in human blood. Finally increases in total monocytes and fibrocytes correlated with asthma severity.
Supervisor: Not available Sponsor: Kind Saud University ; Saudi Arabian Cultural Bureau in London
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Asthma ; Monocytes ; Fibroblasts