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Title: Is occupational asbestos exposure an under-recognised cause of idiopathic pulmonary fibrosis?
Author: Reynolds, Carl
ISNI:       0000 0005 0287 338X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2020
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The question of whether occupational asbestos exposure is an under- recognized cause of idiopathic pulmonary fibrosis arises because it is clinically and epidemiologically plausible, and consistent with fibre studies, case-control, and toxicological data. This thesis examines the question by means of a literature review and a novel hospital based case-control study, the idiopathic pulmonary fibrosis job exposures study (IPFJES). In a literature review and meta-analysis of studies reporting on occupational exposures in idiopathic pulmonary fibrosis (IPF) I found significant associ- ations with metal, wood, and stone dust, but not asbestos. However, there was considerable heterogeneity and confidence in the meta-analysis result is tempered by a high risk of bias arising from selection, lack of blinding, exposure misclassification, incomplete exposure data, and selective report- ing of exposures. In a mortality analysis I found that the UK incidence of IPF continues to rise and appears to be correlated with mesothelioma mor- tality. I did not find clear evidence of an association between IPF, pleural mesothelioma, and asbestosis at a regional level. In a critical review of methods for assessing occupational asbestos exposure I found support for the use of a job exposure matrix based on proportional mortality rates for mesothelioma and validated by quantification of asbestos fibre lung burden. I also found support for using a structured interview tool to provide a quantitative estimate of previous exposure which was validated using historic and simulated exposure data. In a review of MUC5b and IPF I found evidence supporting a common MUC5b driven pulmonary fibrosis endotype and a candidate mechanism for 3occupational asbestos exposure contributing to this; alveolar macrophage NLRP3 inflammasome activation resulting in increased IL-1 β driven airway MUC5b expression. Occupational asbestos exposure alone was not associated with IPF in IPF- JES. It was associated with dyspnoea independent of smoking and case status. It was associated with IPF in participants who also had smoking exposure and the strength of this association was greatest for participants with the minor allele of the MUC5b promoter variant rs3505950 and when a stricter case definition (definite UIP rather than definite UIP or possible UIP) was used. These studies suggest that occupational asbestos exposure in smokers, cou- pled with genetic susceptibility factors, may be an important cause of IPF.
Supervisor: Cullinan, Paul Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral