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Investigation of fibulin-2 in pulmonary fibrosis

Pearce, David; (2021) Investigation of fibulin-2 in pulmonary fibrosis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Pulmonary fibrosis is a chronic and progressive scarring of the lungs for which there is no adequate therapy. Epigenetic mechanisms have been identified in the persistence of phenotype seen in explanted fibrotic fibroblast cells. Gene methylation and expression in fibrotic fibroblasts was compared to that of non-diseased controls and, through progressive filtering, fibulin-2 was identified as a potential gene of interest in pulmonary fibrosis. Fibulin-2 is an extracellular matrix (ECM) glycoprotein which binds numerous other ECM components and competes with the sequestering of latent transforming growth factor (TGF)-β into the matrix. Fibulin-2 expression may be up- or down-regulated in tumours, and in breast cancer and nasopharyngeal carcinoma downregulation is associated with CpG hypermethylation. Its expression is upregulated during wound healing and fibrosis in several organs. In addition, deletion of fibulin-2 is protective in animal models of cardiac fibrosis. However, there is little information on the role and regulation of fibulin-2 in pulmonary fibrosis. Expression of FBLN2 was increased in fibrotic lung fibroblasts compared to controls and methylation analysis identified both hypo- and hyper-methylation of FBLN2 which correlated with its expression. Immunohistochemical staining showed fibulin-2 localised predominantly to the alveolar interstitium, airway and vessel walls. Additionally, fibrotic lung tissue showed widespread diffuse staining associated with areas of ECM deposition. In 2D and 3D in vitro models, fibulin-2 was strongly expressed and deposited by fibrotic lung fibroblasts and upregulated by treatment with TGFβ1. Control cells, however, produced comparatively little fibulin-2. Knockdown of FBLN2 expression by siRNA reduced the fibrotic markers collagen I and α smooth muscle actin in fibrotic lung fibroblasts in these models. The results in this thesis demonstrate a potential role for fibulin-2 in the continued pathogenesis of pulmonary fibrosis and may represent a novel therapeutic target in the disease.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigation of fibulin-2 in pulmonary fibrosis
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10133999
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