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Investigating the role of vitamin A and retinoic acid signalling in lung homeostasis and repair

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Title: Investigating the role of vitamin A and retinoic acid signalling in lung homeostasis and repair
Authors: Mongey, Roisin
Item Type: Thesis or dissertation
Abstract: The human lung is capable of endogenous repair, but the underlying mechanisms which control this remain unclear. Many of the processes involved in lung repair are thought to be similar to those required during alveolar development. As such, the targeting of factors involved in lung development provides a potential therapeutic route for the induction of endogenous repair mechanisms. Retinoic acid (RA), obtained wholly from dietary vitamin A (vit A), is an essential mediator of lung development and can promote regeneration in experimental animal models of alveolar insufficiency. We aimed to investigate the role of RA in mediating lung structural homeostasis and repair using a multi-disciplinary, epidemiological and lab-based approach. We identified a positive role for dietary vit A in the modulation of adult lung function in a large UK population-based study. Using genetic data from this study, we have also identified single nucleotide polymorphisms (SNPs) in RA pathway genes that modulate lung function, some of which interact with vit A intake. At a cellular level, we used an in vitro scratch assay model to show that treatment with exogenous RA directly promotes endothelial repair but does not affect epithelial repair, either directly or via paracrine signalling from the endothelium. To study the role of RA in 3D alveolar tissue, we developed the acid injury and repair (AIR) model, a novel ex vivo tool in which the response to injury and subsequent repair mechanisms can be determined. By examining established cellular markers of repair in the AIR model, we discovered that the number of progenitor cells increases in damaged regions of tissue whereas in the uninjured areas of the same PCLS, proliferation increases without a concomitant increase in progenitor cells. Manipulation of RA signalling using pharmacological inhibitors resulted in a significant reduction in proliferation following injury. RA reporter mice, which express GFP linked to the RA response element, were used to visualise active RA signalling. By combining this reporter line with the AIR model, we found GFP expression, indicative of active RA signalling, in postnatal day 7 PCLS and observed an increase in GFP signal following injury in adult PCLS. Overall, our findings suggest that RA signalling primarily affects the capillary endothelium during lung repair and that at a population level, a vit A rich diet could be used to modify lung function. Together this multidisciplinary approach provides important insight into the mechanisms underlying the role of RA in lung repair and regeneration and suggests that regulation of vitamin A levels through nutritional intake may provide a route to help maintain adult lung function. 
Content Version: Open Access
Issue Date: Jan-2021
Date Awarded: May-2021
URI: http://hdl.handle.net/10044/1/90134
DOI: https://doi.org/10.25560/90134
Copyright Statement: Creative Commons Attribution NonCommercial No Derivatives Licence
Supervisor: Hind, Matthew
Dean, Charlotte
Minelli, Cosetta
Sponsor/Funder: Royal Brompton and Harefield NHS Foundation Trust
Funder's Grant Number: WHRL_P64410
Department: National Heart & Lung Institute
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:National Heart and Lung Institute PhD theses



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