The impact of methylarginine metabolism on disease progression in idiopathic pulmonary fibrosis
File(s)
Author(s)
Lota, Harpreet Kaur
Type
Thesis
Abstract
Idiopathic pulmonary fibrosis (IPF) is a complex, progressive and irreversible lung disease of unknown aetiology with a median survival of only three years following diagnosis. Signatures of increased nitric oxide (NO) and its generating enzyme, inducible nitric oxide synthase (iNOS), are observed in experimental models of idiopathic pulmonary fibrosis (IPF). Asymmetric dimethylarginine (ADMA) competitively inhibits iNOS, and is hydrolysed by dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2. Previous evidence suggests that regulation of NO production via DDAH activity may play a role in IPF. Using both in vitro and human studies, this project investigated the relationship between the NO-ADMA-DDAH pathway and the progression of lung fibrosis; more specifically that variation in DDAH activity will impact on disease progression in IPF.
The in vitro study aimed to identify the mechanistic pathways linking DDAH activity to lung fibrosis in an experimental model of transforming growth factor-β (TGF-β) mediated epithelial to mesenchymal transition (EMT) in a human alveolar epithelial cell line. DDAH2 and iNOS were induced during TGF-β mediated EMT, indicating that DDAH may play a role in the transition towards the fibrotic phenotype. The human study aimed to identify the impact of DDAH single nucleotide polymorphisms (SNPs) with a known functional effect on ADMA levels in a normal cohort on longitudinal lung function decline and survival in a cohort of IPF patients. The results indicated that DDAH1 variant rs530006 (associated with lower ADMA levels in a normal cohort) was significantly associated with accelerated lung function decline and mortality in the IPF cohort. DDAH2 SNPs were not associated with lung function decline or mortality in the IPF cohort. Neither DDAH1 or DDAH2 SNPs were associated with lung function decline in a large cohort of patients with systemic sclerosis associated interstitial lung disease (SSc-ILD), supportive of the genetic distinction that is emerging between the two fibrotic lung diseases.
Overall, the evidence accumulated provides some novel insights into the potential role of DDAH in IPF. The complicated relationship between inherited genetic variants and environmental factors is a growing field in IPF, and DDAH biology may be one of the multiple pathways that leads to the fibrotic phenotype that we know as IPF.
The in vitro study aimed to identify the mechanistic pathways linking DDAH activity to lung fibrosis in an experimental model of transforming growth factor-β (TGF-β) mediated epithelial to mesenchymal transition (EMT) in a human alveolar epithelial cell line. DDAH2 and iNOS were induced during TGF-β mediated EMT, indicating that DDAH may play a role in the transition towards the fibrotic phenotype. The human study aimed to identify the impact of DDAH single nucleotide polymorphisms (SNPs) with a known functional effect on ADMA levels in a normal cohort on longitudinal lung function decline and survival in a cohort of IPF patients. The results indicated that DDAH1 variant rs530006 (associated with lower ADMA levels in a normal cohort) was significantly associated with accelerated lung function decline and mortality in the IPF cohort. DDAH2 SNPs were not associated with lung function decline or mortality in the IPF cohort. Neither DDAH1 or DDAH2 SNPs were associated with lung function decline in a large cohort of patients with systemic sclerosis associated interstitial lung disease (SSc-ILD), supportive of the genetic distinction that is emerging between the two fibrotic lung diseases.
Overall, the evidence accumulated provides some novel insights into the potential role of DDAH in IPF. The complicated relationship between inherited genetic variants and environmental factors is a growing field in IPF, and DDAH biology may be one of the multiple pathways that leads to the fibrotic phenotype that we know as IPF.
Version
Open Access
Date Issued
2018-02
Date Awarded
2018-07
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Lieper, James
Rueda Armada, David
Sponsor
Medical Research Council (Great Britain)
Publisher Department
London Institute of Medical Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Medicine (Research) MD (Res)