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Tissue and extracellular matrix remodelling in pulmonary fibrosis and chronic lung allograft dysfunction

Svobodová, Barbora LU (2025) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
In recent years, the prevalence of idiopathic pulmonary fibrosis (IPF) and post-COVID-19 pulmonary fibrosis has risen. Nevertheless, effective diagnostic and prognostic biomarkers alongside targeted treatments are lacking, making lung transplantation the last resort for many patients with end-stage disease. However, bronchiolitis obliterans syndrome (BOS), a manifestation of chronic lung allograft dysfunction (CLAD), limits long-term survival post-transplantation. Despite the clinical significance of IPF, post-COVID-19 lung fibrosis, and BOS, the underlying molecular mechanisms driving these conditions remain incompletely understood.
This research aimed to deepen our understanding of tissue remodelling and extracellular matrix (ECM)... (More)
In recent years, the prevalence of idiopathic pulmonary fibrosis (IPF) and post-COVID-19 pulmonary fibrosis has risen. Nevertheless, effective diagnostic and prognostic biomarkers alongside targeted treatments are lacking, making lung transplantation the last resort for many patients with end-stage disease. However, bronchiolitis obliterans syndrome (BOS), a manifestation of chronic lung allograft dysfunction (CLAD), limits long-term survival post-transplantation. Despite the clinical significance of IPF, post-COVID-19 lung fibrosis, and BOS, the underlying molecular mechanisms driving these conditions remain incompletely understood.
This research aimed to deepen our understanding of tissue remodelling and extracellular matrix (ECM) alterations, particularly within the lung epithelial-mesenchymal niches, that contribute to pulmonary fibrosis and CLAD/BOS. Using histological and molecular analyses at both RNA and protein levels in human lung tissue, we identified previously unrecognized ECM and ECM-associated molecules that appear to play a role in end-stage IPF and post-COVID-19 fibrosis, as well as airway remodelling in BOS.
Notably, increased collagen VII expression was observed in pathologically remodelled alveolar and airway structures in IPF, with basal cells and aberrant basaloid cells identified as the primary cell types expressing collagen VII. In BOS-affected small airways, altered levels of periostin, known for its role in fibroblast activation and collagen fibrillogenesis, as well as changed levels of LOX and LOXL1, enzymes involved in the covalent cross-linking of structural ECM components such as collagen and elastin, were found. Although IPF and post-COVID-19 fibrosis are triggered by different factors, shared patterns of in situ lung remodelling were identified, including altered periostin and LAMP3 expression, alongside systemic protein alterations. These findings highlight potential molecular targets for further investigations.
This thesis provides novel insights into the complex molecular landscape of pathological lung microenvironments driving pulmonary and airway fibrosis. Expanding this knowledge may pave the way for improved understanding of disease pathogenesis, ultimately leading to better diagnostic and prognostic tools and novel therapeutic strategies.
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author
supervisor
opponent
  • Associate Professor Staab-Weijnitz, Claudia, University of Colorado, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Idiopathic pulmonary fibrosis, Post-COVID-19, Chronic lung allograft dysfunction, Bronchiolitis obliterans syndrome, lung fibrosis, remodelling, extracellular matrix, basal cells, fibroblasts
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2025:55
pages
72 pages
publisher
Lund University, Faculty of Medicine
defense location
BMC I1345, Sölvegatan 19 i Lund
defense date
2025-05-13 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-708-8
language
English
LU publication?
yes
id
66b9ecf7-2d84-48b4-b913-c3f06c427625
date added to LUP
2025-04-22 23:19:40
date last changed
2025-04-25 10:03:20
@phdthesis{66b9ecf7-2d84-48b4-b913-c3f06c427625,
  abstract     = {{In recent years, the prevalence of idiopathic pulmonary fibrosis (IPF) and post-COVID-19 pulmonary fibrosis has risen. Nevertheless, effective diagnostic and prognostic biomarkers alongside targeted treatments are lacking, making lung transplantation the last resort for many patients with end-stage disease. However, bronchiolitis obliterans syndrome (BOS), a manifestation of chronic lung allograft dysfunction (CLAD), limits long-term survival post-transplantation. Despite the clinical significance of IPF, post-COVID-19 lung fibrosis, and BOS, the underlying molecular mechanisms driving these conditions remain incompletely understood.<br/>This research aimed to deepen our understanding of tissue remodelling and extracellular matrix (ECM) alterations, particularly within the lung epithelial-mesenchymal niches, that contribute to pulmonary fibrosis and CLAD/BOS. Using histological and molecular analyses at both RNA and protein levels in human lung tissue, we identified previously unrecognized ECM and ECM-associated molecules that appear to play a role in end-stage IPF and post-COVID-19 fibrosis, as well as airway remodelling in BOS. <br/>Notably, increased collagen VII expression was observed in pathologically remodelled alveolar and airway structures in IPF, with basal cells and aberrant basaloid cells identified as the primary cell types expressing collagen VII. In BOS-affected small airways, altered levels of periostin, known for its role in fibroblast activation and collagen fibrillogenesis, as well as changed levels of LOX and LOXL1, enzymes involved in the covalent cross-linking of structural ECM components such as collagen and elastin, were found. Although IPF and post-COVID-19 fibrosis are triggered by different factors, shared patterns of in situ lung remodelling were identified, including altered periostin and LAMP3 expression, alongside systemic protein alterations. These findings highlight potential molecular targets for further investigations.<br/>This thesis provides novel insights into the complex molecular landscape of pathological lung microenvironments driving pulmonary and airway fibrosis. Expanding this knowledge may pave the way for improved understanding of disease pathogenesis, ultimately leading to better diagnostic and prognostic tools and novel therapeutic strategies.<br/>}},
  author       = {{Svobodová, Barbora}},
  isbn         = {{978-91-8021-708-8}},
  issn         = {{1652-8220}},
  keywords     = {{Idiopathic pulmonary fibrosis; Post-COVID-19; Chronic lung allograft dysfunction; Bronchiolitis obliterans syndrome; lung fibrosis; remodelling; extracellular matrix; basal cells; fibroblasts}},
  language     = {{eng}},
  number       = {{2025:55}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Tissue and extracellular matrix remodelling in pulmonary fibrosis and chronic lung allograft dysfunction}},
  url          = {{https://lup.lub.lu.se/search/files/217702219/Barbora_Svobodova_Doctoral_thesis.pdf}},
  year         = {{2025}},
}