Understanding the role of airway epithelial cell metabolism during chronic lung disease
File(s)
Author(s)
Calamita, Emily Theresa
Type
Thesis
Abstract
Interstitial lung diseases (ILDs) are often fatal chronic lung diseases (CLDs) with limited treatment options. Idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP) are the most common ILDs and are characterised by damaged lung architecture, excessive inflammation and interstitial extracellular matrix deposition which compromise lung function. Epithelial injury is a defining feature of ILDs, however specific pathways which regulate epithelial dysfunction in ILD are not clear. Altered central carbon metabolism has been identified in ILD, yet the metabolism of bronchial epithelial cells (BECs), their phenotype and contribution during ILD pathogenesis is poorly understood.
I therefore hypothesized that BECs from CLDs such as ILDs have an altered central carbon metabolism, and that these changes in metabolism underlie function, thereby contributing to disease pathogenesis.
From profiling bronchoalveolar lavage by GCMS, flow-cytometry and multiplex assays, I identified a metabolically, cellularly and molecularly distinct lung environment in HP and IPF compared to healthy control (HC), indicative of disrupted epithelial function. By ex vivo functional assessment, BECs from HP patients had abnormal wound healing responses and an altered central carbon metabolism, characterised by reduced respiration, reduced metabolic flexibility, and increased aldolase activity. As determined by pharmacological inhibition and metabolite supplementation, changes in environmental and cellular metabolism had functional relevance affecting wound closure, IL-6 release, and differentiation, therefore underlying aspects of abnormal HP BEC function. Central carbon metabolism associated transcriptome and methylation signatures were altered in HP, suggesting a mechanism of regulation. Metabolic perturbance correlated with reduced lung function, implicating a role in disease outcome.
These data indicate that there are specific metabolic alterations in HP, these have a functional consequence, and disease relevancy. These data also have wider implications in the targeting of BECs therapeutically in the treatment of CLDs.
I therefore hypothesized that BECs from CLDs such as ILDs have an altered central carbon metabolism, and that these changes in metabolism underlie function, thereby contributing to disease pathogenesis.
From profiling bronchoalveolar lavage by GCMS, flow-cytometry and multiplex assays, I identified a metabolically, cellularly and molecularly distinct lung environment in HP and IPF compared to healthy control (HC), indicative of disrupted epithelial function. By ex vivo functional assessment, BECs from HP patients had abnormal wound healing responses and an altered central carbon metabolism, characterised by reduced respiration, reduced metabolic flexibility, and increased aldolase activity. As determined by pharmacological inhibition and metabolite supplementation, changes in environmental and cellular metabolism had functional relevance affecting wound closure, IL-6 release, and differentiation, therefore underlying aspects of abnormal HP BEC function. Central carbon metabolism associated transcriptome and methylation signatures were altered in HP, suggesting a mechanism of regulation. Metabolic perturbance correlated with reduced lung function, implicating a role in disease outcome.
These data indicate that there are specific metabolic alterations in HP, these have a functional consequence, and disease relevancy. These data also have wider implications in the targeting of BECs therapeutically in the treatment of CLDs.
Version
Open Access
Date Issued
2024-07-15
Date Awarded
2025-04-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Byrne, Adam J
Lloyd, Clare M
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)