The University of Southampton
University of Southampton Institutional Repository

A characterisation of fibrolastic foci and their production of fibrillar collagens in idiopathic pulmonary fibrosis

A characterisation of fibrolastic foci and their production of fibrillar collagens in idiopathic pulmonary fibrosis
A characterisation of fibrolastic foci and their production of fibrillar collagens in idiopathic pulmonary fibrosis
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.
University of Southampton
Jones, Mark G.
a1264258-5fa5-4063-95e1-d7ff7c52a2de
Jones, Mark G.
a1264258-5fa5-4063-95e1-d7ff7c52a2de
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Richeldi, Luca
47177d9c-731a-49a1-9cc6-4ac8f6bbbf26
O'reilly, Karen
a0812526-81b1-4cc3-b1df-eab66e9e1abe

Jones, Mark G. (2016) A characterisation of fibrolastic foci and their production of fibrillar collagens in idiopathic pulmonary fibrosis. University of Southampton, Doctoral Thesis, 253pp.

Record type: Thesis (Doctoral)

Abstract

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.

Text
Mark Jones Final Thesis - Version of Record
Restricted to Repository staff only until 22 February 2020.
Available under License University of Southampton Thesis Licence.

More information

Published date: September 2016

Identifiers

Local EPrints ID: 434991
URI: https://eprints.soton.ac.uk/id/eprint/434991
PURE UUID: cf126a91-f708-4b42-846b-1a4d3e8b2e45
ORCID for Donna Davies: ORCID iD orcid.org/0000-0002-5117-2991

Catalogue record

Date deposited: 17 Oct 2019 16:30
Last modified: 18 Oct 2019 00:39

Export record

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×