Open Research Newcastle
Browse

Role of fibulin1 in the pathogenesis of chronic pulmonary diseases

thesis
posted on 2025-05-09, 11:44 authored by Gang Liu
Airway and/or lung remodelling, involving exaggerated extracellular matrix (ECM) protein deposition, is a critical feature common to pulmonary diseases including chronic obstructive pulmonary disease (COPD), asthma and idiopathic pulmonary fibrosis (IPF). Fibulin (Fbln)-1, an important ECM protein involved in matrix organisation, may be involved in the pathogenesis of these diseases. We found that Fbln1 was increased in COPD patients and in cigarette smoke (CS)-induced experimental COPD in mice. Genetic or therapeutic inhibition of Fbln1c protected against CS-induced airway fibrosis, emphysema-like alveolar enlargement and impaired lung function. In our experimental COPD model, this occurred as the Fbln1c–/– mice were protected against increased collagen deposition around the airways and reduced collagen deposition in the parenchyma. In addition, we found that Fbln1c interacts with fibronectin (Fn), periostin (Postn) and tenascin-c (Tnc) to regulate collagen deposition. Genetic inhibition of Fbln1c also reduced levels of pulmonary inflammatory cells and proinflammatory cytokines/chemokines (TNF-α, IL-33, and CXCL1) in experimental COPD. Fbln1 levels were increased in house dust mite induced experimental chronic asthma in mice. The deficiency of Fbln1c in mice protected against airway remodelling and airway hyperresponsiveness, although it did not affect mucus production. Fbln1c also interacted with Fn, Tnc and Postn to affect collagen deposition in experimental asthma. Fbln1c–/– mice had reduced inflammatory cells in the airways, and decreased levels of TNF-α, IL-33, and CXCL1 in experimental chronic asthma. Fbln1 was also increased in bleomycin-induced experimental lung fibrosis in mice. Fbln1c–/– mice had reduced airway remodelling and lung fibrosis, and were protected against impaired lung function after bleomycin challenge. In experimental lung fibrosis, Fbln1 interacted with Fn, Postn and Tnc to affect collagen deposition. Fbln1c–/– mice also had less inflammatory cells, as well as TGF-β and IL-33 levels in the lungs compared to wild-type mice in an experimental model of lung fibrosis. Taken together, our data show that Fbln1c may be a therapeutic target in chronic respiratory diseases.

History

Year awarded

2016.0

Thesis category

  • Doctoral Degree

Degree

Doctor of Philosophy (PhD)

Supervisors

Hansbro, Phil (University of Newcaslte); Foster, Paul (University of Newcaslte); Horvat, Jay (University of Newcaslte); Jarnicki, Andrew (University of Newcaslte); Burgess, Janette (University of Sydney)

Language

  • en, English

College/Research Centre

Faculty of Health and Medicine

School

School of Biomedical Sciences and Pharmacy

Rights statement

Copyright 2016 Gang Liu

Usage metrics

    Theses

    Categories

    No categories selected

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC