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Title: A characterisation of fibrolastic foci and their production of fibrillar collagens in idiopathic pulmonary fibrosis
Author: Jones, Mark G.
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2016
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Idiopathic pulmonary fibrosis (IPF) is a complex chronic fibroproliferative disease of unknown aetiology where aggregates of highly active fibroblasts, termed 'fibroblastic foci', produce excessive extracellular matrix (ECM) components. On standard 2D pathologic examination fibroblastic foci are considered small, distinct lesions although in 3D they have been proposed to form a highly interconnected reticulum as the leading edge of a "wave" of active fibrosis. There is increasing recognition that the ECM produced may not simply be a consequence of fibrosis but may also contribute to fibrogenesis, however the actual changes in ECM structure and function remain poorly understood. This thesis will further study fibroblastic foci and the predominant ECM constituent, fibrillar collagen, in IPF. Fibroblastic focus morphology and inter-relationships in 3D were studied by integrated microCT and histological analyses. Collagen expression in ex vivo IPF lung tissue was characterised by biochemical, biomechanical, histological, and non-linear imaging analyses. A long term model of fibrillar collagen production by fibroblastic foci was established using parenchymal lung fibroblasts explanted from IPF or non-fibrotic lung tissue. This study demonstrates that the application of multi-modal imaging methodologies can further advance concepts of disease pathogenesis in fibrotic lung diseases. It provides novel data that in 3D fibroblastic foci are heterogeneous and of varying size and complexity, suggesting previously unrecognised plasticity. It also shows that these fibroblastic structures are independent of each other, consistent with their being the product of discrete sites of lung injury and repair. It demonstrates that in IPF posttranslational modifications of collagen, rather than increased total collagen content, strongly influence the altered mechanical properties of IPF lung tissue, and identifies upregulation of multiple lysyl oxidases as therapeutic targets. Finally, it describes a novel 3D model culture system of fibroblastic focus ECM production with utility in mechanistic and therapeutic studies of fibrotic lung diseases.
Supervisor: Davies, Donna ; Richeldi, Luca ; O'Reilly, Karen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available