Delineating the dual roles of leukotriene A4 hydrolase in the context of interstitial lung diseases
File(s)
Author(s)
Suveizdyte, Kornelija
Type
Thesis
Abstract
The enzyme leukotriene A4 hydrolase (LTA4H) functions to generate the pro-inflammatory lipid mediator leukotriene B4 (LTB4) and to degrade the extracellular matrix collagen derived tripeptide Proline-Glycine-Proline (PGP). During acute, self-resolving inflammation PGP bioavailability is tightly regulated by LTA4H. However, persistence of PGP results in chronic neutrophilia and pathological airway epithelial remodelling in chronic lung diseases. The aim of this thesis was to investigate dual roles of LTA4H in the context of interstitial lung diseases (ILDs) which are characterised by an aberrant alveolar epithelial repair, excessive extracellular matrix deposition and fibrosis.
In Chapter 3 I demonstrated that LTB4 accumulated in the airways of ILD patients. However, PGP and AcPGP were completely absent from the airways of ILD patients, possibly due to degradation of PGP by significantly elevated levels of extracellular LTA4H.
In Chapter 4 I show that PGP/AcPGP is able to induce bronchial epithelial proliferation via the CXCR1/2 and EGF signalling, and that PGP can act on alveolar epithelial cells to promote wound healing responses.
In Chapter 5 I demonstrated that specific loss of LTB4 signalling reduced fibrosis in a mouse model of bleomycin induced fibrosis. However, mice lacking LTA4H had increased early airway neutrophilia and comparable fibrosis to their littermates. I rationalised PGP fulfils divergent effects as administration of PGP concomitantly with bleomycin to wild type mice resulted in enhanced neutrophilia. Conversely, delayed treatment with PGP ameliorated lung fibrosis.
In Chapter 6 I demonstrated that airway LTA4H levels were elevated in patients with post- COVID-19 syndrome and the imbalance between PGP generating and degrading enzymes correlated with the level of lung opacity as defined by CT scan.
Combined, this thesis provides insights into the dual roles of enzyme LTA4H in lung repair and fibrosis. I suggest that increased degradation of PGP potentially underlies aberrant epithelial repair and ensuing lung fibrosis.
In Chapter 3 I demonstrated that LTB4 accumulated in the airways of ILD patients. However, PGP and AcPGP were completely absent from the airways of ILD patients, possibly due to degradation of PGP by significantly elevated levels of extracellular LTA4H.
In Chapter 4 I show that PGP/AcPGP is able to induce bronchial epithelial proliferation via the CXCR1/2 and EGF signalling, and that PGP can act on alveolar epithelial cells to promote wound healing responses.
In Chapter 5 I demonstrated that specific loss of LTB4 signalling reduced fibrosis in a mouse model of bleomycin induced fibrosis. However, mice lacking LTA4H had increased early airway neutrophilia and comparable fibrosis to their littermates. I rationalised PGP fulfils divergent effects as administration of PGP concomitantly with bleomycin to wild type mice resulted in enhanced neutrophilia. Conversely, delayed treatment with PGP ameliorated lung fibrosis.
In Chapter 6 I demonstrated that airway LTA4H levels were elevated in patients with post- COVID-19 syndrome and the imbalance between PGP generating and degrading enzymes correlated with the level of lung opacity as defined by CT scan.
Combined, this thesis provides insights into the dual roles of enzyme LTA4H in lung repair and fibrosis. I suggest that increased degradation of PGP potentially underlies aberrant epithelial repair and ensuing lung fibrosis.
Version
Open Access
Date Issued
2023-04-27
Date Awarded
01/03/2024
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Snelgrove, Robert
Byrne, Adam
Maher, Toby
Sponsor
Wellcome Trust (London, England)
National Heart and Lung Institute
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)