uPAR regulates bronchial epithelial repair in vitro and is elevated in asthmatic epithelium

Abstract

BackgroundThe asthma-associated gene urokinase plasminogen activator receptor (uPAR) may be involved in epithelial repair and airway remodelling. These processes are not adequately targeted by existing asthma therapies. A fuller understanding of the pathways involved in remodelling may lead to development of new therapeutic opportunities. uPAR expression in the lung epithelium of normal subjects and patients with asthma was investigated and the contribution of uPAR to epithelial wound repair in vitro was studied using primary bronchial epithelial cells (NHBECs).MethodsBronchial biopsy sections from normal subjects and patients with asthma were immunostained for uPAR. NHBECs were used in a scratch wound model to investigate the contribution of the plasminogen pathway to repair. The pathway was targeted via blocking of the interaction between urokinase plasminogen activator (uPA) and uPAR and overexpression of uPAR. The rate of wound closure and activation of intracellular signalling pathways and matrix metalloproteinases (MMPs) were measured.ResultsuPAR expression was significantly increased in the bronchial epithelium of patients with asthma compared with controls. uPAR expression was increased during wound repair in monolayer and air-liquid interface-differentiated NHBEC models. Blocking the uPA–uPAR interaction led to attenuated wound repair via changes in Erk1/2, Akt and p38MAPK signalling. Cells engineered to have raised levels of uPAR showed attenuated repair via sequestration of uPA by soluble uPAR.ConclusionsThe uPAR pathway is required for efficient epithelial wound repair. Increased uPAR expression, as seen in the bronchial epithelium of patients with asthma, leads to attenuated wound repair which may contribute to the development and progression of airway remodelling in asthma. This pathway may therefore represent a potential novel therapeutic target for the treatment of asthma.

Translating Lung Function Genome-Wide Association Study (GWAS) Findings

“…(Portelli et al, 2014). This fits well with the observation of elevated levels of PLAUR in the airway epithelium in asthma patients (Stewart et al, 2012) and association of PLAUR levels with worsening prognosis and increased disease aggressiveness in other diseases such as cancer and COPD (Ivancso et al, 2013;Smith & Marshall, 2010). However it is difficult to infer completely the functional role of the gene with an overexpression approach and gene depletion is potentially more informative from this perspective.…”

“…A good example is the recent protein eQTL analyses of serum urokinase plasminogen activator receptor (suPAR) levels (Portelli et al, 2014). uPAR has been identified as an asthma susceptibility gene (Barton et al, 2009) and has been shown to be differentially expressed in the airways (Stewart, Nijmeh, Brightling, & Sayers, 2012) and blood (Portelli et al, 2014) in asthma patients. The receptor exists as a glycosyl-phosphatidylinositol (GPI)-linked receptor and is involved in a wide range of functions including migration, proliferation and adhesion and is also involved in fibrinolysis (Portelli et al, 2014).…”

TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation

“…RNA profiling of AECs revealed that the gene whose expression in these cells was most affected by the absence of TNFR1/2 was Plaur, which encodes uPAR, a serine protease receptor involved in the generation of plasmin from plasminogen. Previous genetic (34) and biological (43,44) evidence has strongly implicated uPAR in asthma, particularly in severe, nonatopic asthma. Our current work shows that Plaur expression in AECs is dependent on TNF signaling responses in those cells.…”

Involvement of urokinase in cigarette smoke extract-induced epithelial–mesenchymal transition in human small airway epithelial cells

“…21,22 We hypothesized that endogenous production of uPAR in uPA-overexpressing HSAEpiC cells may be necessary to sustain EMT. To test this hypothesis, we transfected uPA-overexpressing and control HSAEpiC cells with the uPAR shRNA silencing vector, pSuper-shuPAR.…”