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Title: An investigation into the contribution of airway cells to the pathogenesis of idiopathic pulmonary fibrosis
Author: Toshner, Richard
ISNI:       0000 0004 7963 7919
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Idiopathic pulmonary fibrosis(IPF) is a debilitating lung disease leading to progressive destruction of the alveolar parenchyma. It is believed to be the result of an uncontrolled wound healing response triggered by repetitive injury to the alveolar epithelium and a self-propagating cycle of epithelial cell injury, fibroblast activation and collagen deposition. The hypothesis explored here is that airway macrophage and bronchial epithelial cell dysfunction contributes to the fibrotic process in the IPF lung, in part through the regulation of the IL-33/ST2 signalling axis. This hypothesis was investigated by examination of airway macrophage phenotype by flow cytometry, and characterisation of gene expression and in vitro function at baseline and in response to stimulation of cultured human bronchial epithelial cells (HBECs) and lung fibroblasts. These data demonstrated that airway macrophages(AMs) in IPF and healthy control volunteers exhibit a complex spectrum of activation and do not conform to the bipolar M1/M2 paradigm of macrophage polarisation. AMs exhibit high levels of expression of both M1 and M2 markers and no difference was found when comparing marker expression between IPF and healthy control. Results of bronchial epithelial phenotyping were in accordance with a body of work suggesting the IPF lung to be a mucin rich environment, with an increase in the expression of MUC5AC expressing airway cells. This work also found an increase in SCGB1A1 expressing club cells in bronchioles in IPF when compared to healthy control lung tissue. This study did not find in vitro functional differences of IPF HBECs when examining proliferation, tight junction formation, barrier function, or direct effect on fibroblast extracellular matrix(ECM) regulation. Aside from an increase, in gene expression of a negative regulator of the IL-33 signalling axis (SIGIRR)in IPF HBECs compared to healthy control - this study not demonstrate any differences in IL-33/ST2 axis expression in airway, tissue or in the alveolar space in IPF. This work did not demonstrate evidence to support the hypothesis that AMs and HBECs contribute to the development of IPF and did not show any direct pro-fibrotic effects of the IL-33/ST2 signalling axis in IPF.
Supervisor: Maher, Toby ; Lloyd, Clare ; Byrne, Adam Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral