Biology subjects

Molyneaux, P.

Publications and source records attributed to Molyneaux, P..

4 recordsLinked to original sources

bioRxiv2023

Adventitial mast cell activation disrupts endothelial cell/pericyte interactions during early life allergic asthma

Allergic asthma generally starts during early life and is linked to substantial tissue remodelling and lung dysfunction. Although angiogenesis is a feature of the disrupted airway, the impact of allergic asthma on the pulmonary microcirculation during early life is unknown. Here, using quantitative imaging in precision-cut lung slices (PCLS), we report that exposure of neonatal mice to house dust mite (HDM) extract disrupts endothelial cell/pericyte interactions in adventitial areas. Central to the blood vessel structure, the loss of pericyte coverage was driven by mast cell (MCs) proteases, such as tryptase, that can induce pericyte retraction and loss of the critical adhesion molecule N-Cadherin. Furthermore, spatial transcriptomics of paediatric asthmatic endobronchial biopsies suggests intense vascular stress and remodelling linked with increased expression of MC activation pathways in regions enriched in blood vessels. These data provide previously unappreciated insights into the pathophysiology of allergic asthma with potential long-term vascular defects.

immunology↗

bioRxiv2020

Epigenetic alterations underlie airway macrophage differentiation and phenotype during lung fibrosis

Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, the epigenetics of AMs development and function in IPF are limited. Here, we characterised the DNA-methylation (DNAm) profile of AMs from IPF (n=30) and healthy (n=14) donors. Our analysis revealed epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm clock analysis indicated epigenetic alterations in IPF-AMs was not associated with accelerated ageing. In differential DNAm analysis, we identified numerous differentially methylated positions (DMPs, n=11) and regions (DMRs, n=49) between healthy and IPF AMs respectively. DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKB3) metabolism and importantly, DNAm status was associated with disease severity in IPF. Collectively, our data identify that profound changes in the epigenome underpin the development and function of AMs in the IPF lung.

immunology↗

bioRxiv2020

Identification of a novel missense variant in SPDL1 associated with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite significant progress, the genetic determinants of this disease remain incompletely defined. Using next generation sequencing data from 752 individuals with sporadic IPF and 119,055 controls, we performed both variant- and gene-level analyses to identify novel IPF genetic risk factors. Our variant-level analysis revealed a novel rare missense variant in SPDL1 (NM_017785.5 p.Arg20Gln; p = 2.4 x 10-7, odds ratio = 2.87). This signal was independently replicated in the FinnGen cohort (combined p = 2.2 x 10-20), firmly associating this variant as a novel IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. Our results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.

genetics↗

bioRxiv2018

Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort

Idiopathic pulmonary fibrosis (IPF) is characterised by excessive extracellular matrix (ECM) deposition and remodelling. Measuring this activity provides an opportunity to develop tools capable of identifying individuals at-risk of progression. Longitudinal change in markers of ECM synthesis was assessed in 145 newly-diagnosed individuals with IPF. Serum levels of collagen synthesis neoepitopes, PRO-C3 and PRO-C6 (collagen type 3 and 6), were elevated in IPF compared with controls at baseline, and progressive disease versus stable disease during follow up, (PRO-C3 p<0.001; PRO-C6 p=0.029). Assessment of rate of change in neoepitope levels from baseline to 3 months (defined as slope to month 3: HIGH slope, slope > 0 vs. LOW slope, slope <=0) demonstrated no relationship with mortality for these markers (PRO-C3 (HR 1.62, p=0.080); PINP (HR 0.76, p=0.309); PRO-C6 (HR 1.14, p=0.628)). As previously reported, rising concentrations of collagen degradation markers C1M, C3M, C6M and CRPM were associated with an increased risk of overall mortality (HR=1.84, CI 1.03 - 3.27, p=0.038, HR=2.44, CI 1.39-4.31, p=0.002; HR= 2.19, CI 1.25-3.82, p=0.006; HR= 2.13 CI 1.21-3.75, p=0.009 respectively). Elevated levels of PRO-C3 and PRO-C6 associate with IPF disease progression. Collagen synthesis and degradation biomarkers have the potential to enhance clinical trials in IPF and may inform prognostic assessment and therapeutic decision making in the clinic.

clinical trials↗