Airway and peripheral uPAR is elevated in asthma, and identifies a severe, non-atopic subset of patients

Abstract

Additional Supporting Information may be found in the online version of this article: Table S1. Clinical and sputum characteristics of lung biopsy groups. Table S2. Demographic information for the Dutch cohort used for serum analyses. Table S3. Demographics information for the UK cohort used for serum analyses. ; RATIONALE: Genetic polymorphisms in the asthma susceptibility gene, urokinase plasminogen activator receptor (uPAR/PLAUR) have been associated with lung function decline and uPAR blood levels in asthma subjects. Preliminary studies have identified uPAR elevation in asthma; however a definitive study regarding which clinical feature of asthma uPAR may be driving is currently lacking. OBJECTIVES: We aimed to comprehensively determine the uPAR expression profile in asthma and control subjects utilising bronchial biopsies and serum, and to relate uPAR expression to asthma clinical features. METHODS: uPAR levels were determined in control (n=9) and asthmatic (n=27) bronchial biopsies using immunohistochemistry, with a semi-quantitative score defining intensity in multiple cell types. Soluble cleaved (sc)uPAR levels were determined in serum through ELISA in UK (cases n=129; controls n=39) and Dutch (cases n=441; controls n=96) cohorts. MEASUREMENTS AND MAIN RESULTS: In bronchial tissue, uPAR was elevated in inflammatory cells in the lamina propria (P=0.0019), bronchial epithelial (P=0.0002) and airway smooth muscle cells (P=0.0352) of asthma patients, with uPAR levels correlated between the cell types. No correlation with disease severity or asthma clinical features was identified. scuPAR serum levels were elevated in asthma patients (1.5 fold; P=0.0008) and we identified an association between high uPAR serum levels and severe, non-atopic disease. CONCLUSIONS: This study provides novel data that elevated airway and blood uPAR in asthma is particularly related to severe, non-atopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population. ; STEPS scholarship part financed by the European Union – European Social Fund (ESF) under Operational Programme II – Cohesion Policy 2007–2013, 'Empowering People for More Jobs and a Better Quality of Life' Asthma UK, Grant 08/017. The study is also part funded by the National Institute for Health Research Leicester Biomedical Research Unit, UK. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or Department of Health. ; Peer-reviewed ; Publisher Version