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Title: The role of epithelial cells and fibroblasts in the pathogenesis of chronic rhinosinusitis
Author: Ball, Stephen Leslie
ISNI:       0000 0004 6499 8308
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2017
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Chronic rhinosinusitis without nasal polyps (CRSsNP) is a heterogeneous condition with common symptoms, clinical and radiological findings. CRSsNP is typified by inflammation of the sinonasal epithelium and development of fibrosis, yet its precise pathophysiology remains elusive. Recently stromal cells have been shown to act like immune effector cells in orchestrating chronic inflammation. Histological analysis of tissue biopsies from patients with CRSsNP demonstrates recruitment of circulating inflammatory cells, though the precise role of structural cells such as epithelial and fibroblast cells in CRSsNP remains to be discovered. Aims 1. (a) Recruit phenotyped cohorts of control & CRSsNP participants. (b) Characterise recruited CRSsNP participants’ tissue samples and isolated epithelial & fibroblast cells. 2. Assay the sinonasal environment to determine any association between, infection, inflammation and remodelling. 3. Identify clusters of genes differentially expressed in CRSsNP & control participants. Methods Cohorts of healthy control and CRSsNP participants were recruited. Matched tissue biopsy, epithelial and fibroblast cells were harvested together with clinical, radiological, microbiological and mucosal swab data. Tissue and cellular samples were characterised to confirm their identity and disease status. The sinonasal environment was characterised from mucosal swabs and analysed for a range of 40 human disease biomarkers. Transcriptome analysis was performed using microarrays and RNA sequencing with downstream bioinformatics investigation of the data. Results 47 age and sex matched CRSsNP and control participants were recruited, differing significantly in symptom and radiological scores. Histological analysis of tissue biopsy specimens was consistent with CRSsNP and control samples. Matched epithelial and fibroblast cells were generated. Assay of the sinonasal microenvironment identified 13 discriminant mediators separating CRSsNP samples from controls using a novel, non-invasive technique. Transcriptomics identified 239 differentially expressed genes in CRSsNP tissue biopsy samples. Cellular samples differed significantly from their matched tissue biopsies. Conclusions This thesis characterises a cohort of tightly defined CRSsNP patients and healthy controls to investigate the potential role of epithelial and fibroblast cells in CRSsNP. Transcriptomics has demonstrated clusters of genes upregulated in CRSsNP, however changes were not consistent in matched cellular samples questioning the validity of cellular models in CRSsNP. Additionally, a straightforward, non-invasive measure of the CRSsNP cytokine profile has been demonstrated. The mediators identified in these assays could potentially be developed as biomarkers of sinonasal inflammation as an adjunct in patient management.
Supervisor: Not available Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available