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Title: Characterisation of the phenotypic and functional repertoire of monocytes in idiopathic pulmonary fibrosis
Author: Fraser, Emily Ruth
ISNI:       0000 0004 7964 406X
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2019
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Idiopathic pulmonary fibrosis (IPF) is a chronic fibroproliferative disease characterised by the accumulation of scar tissue within the lung parenchyma. The pathogenic mechanisms underlying the disease remain incompletely understood but involve aberrations in repair pathways. The role of macrophages in IPF has gained interest due to their recognised contribution in orchestrating repair. In health, lineage tracing has revealed that lung macrophages are established in early development and undergo self- renewal. Following injury however, these populations become depleted and there is evidence from murine models that infiltrating monocytes differentiate into macrophages and potentiate fibrogenic processes. I hypothesised that monocytes may be phenotypically and functionally distinct in IPF and contribute to the process of fibrotic over-repair. To test this, peripheral blood monocytes from IPF patients were immunophenotyped and the expression of genes and proteins associated with inflammatory and repair processes were analysed. Given that IPF exclusively affects the lung tissue, monocytes were differentiated into macrophages using autologous serum to determine whether they expressed pro-repair characteristics. I examined key macrophage functions including ROS generation, phagocytosis and efferocytosis. Lastly, I assessed the influence of monocyte-derived macrophages (MDMs) on fibrogenic endpoints. My data revealed that monocyte levels were higher in IPF patients and correlated with fibrotic burden on CT. CD64 was increased on IPF monocytes and a higher proportion of CD64+CD163- cells underwent early apoptosis. IPF MDMs on day 7 showed greater retention of the monocyte marker CD14, alongside lower CD64 and CD86 expression. ROS generation, phagocytosis and efferocytosis were impaired in IPF MDMs. qPCR of Day 7 MDMs revealed up-regulation of both pro-injury genes, TNFα and STAT1, and pro-repair genes including GR, PPAR-γ, LGALS3 and AREG. Both IPF and control MDMs increased fibroblast proliferation and expression of HAS2, IL-6 and MCP-1 but differences were not observed between groups. MDMs collectively inhibited the process of EMT in an epithelial cell line. The increase in monocyte levels and correlation with fibrotic extent suggests a role for these cells in the pathogenesis of IPF. Impaired efferocytosis and the up-regulation of genes associated with both injurious and reparative processes in IPF MDMs may potentiate tissue damage and promote fibrogenesis in vivo.
Supervisor: Markham, Alexander ; Anwar, Rashida ; Ho, Ling-Pei Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available