Biological mechanisms underlying prematurity-associated lung disease in school-aged children

Course, Christopher 2024. Biological mechanisms underlying prematurity-associated lung disease in school-aged children. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

This thesis uses data collected from the Respiratory Outcomes in Neonates (RHiNO) Study and aimed to identify the underlying mechanisms of prematurity-associated lung disease (PLD) and the effect of inhaler treatments on any implicated biological processes. Exhaled breath condensate (EBC) and urine samples were collected from preterm- and term-born school-aged children both at baseline and after twelve weeks of inhaled therapies. Untargeted proteomic and metabolomic analyses have been used to investigate the mechanisms underlying a range of phenotypes of PLD, based upon neonatal history of bronchopulmonary dysplasia (BPD) and current spirometry patterns, as well as posttreatment effects on any alterations identified. The results demonstrated that preterm-born children with a history of BPD had detectable EBC proteome changes indicative of pulmonary structural alterations, including a reduced abundance of desmosome-constituent proteins. These changes were reversed with combined inhaler therapy (corticosteroid and long-acting β2 agonists), increasing these protein’s abundances to levels comparable to term-born subjects. The EBC metabolome suggested changes in pulmonary antioxidant mechanisms in those with a history of BPD, including significant reductions in metabolites associated with glutathione metabolism, although not revealing any associations with current lung function. Urinary analyses demonstrated proteomic and metabolomic alterations associated with current spirometry patterns. Prematurity-associated obstructive lung disease (POLD) was associated with proteomic changes linked with increases in neutrophil activity and tissueremodelling proteases, with metabolomic changes also suggestive of impairments in glutathione metabolism. The urinary proteome of those with prematurity-associated preserved ratio impaired spirometry (pPRISm)showed changes associated with inflammatory processes and altered T-lymphocyte biology, however minimal metabolomic changes were identified for this group. Overall, these results demonstrated differing biological mechanisms underlying different phenotypes of PLD, including both for those with a history of BPD and those with current impaired lung function results, with evidence that some of these mechanisms are potentially modifiable with inhaled therapies.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	31 January 2025
Last Modified:	31 Jan 2025 16:30
URI:	https://orca.cardiff.ac.uk/id/eprint/175811

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