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Cigarette Smoke Induces uPAR in Vivo and Isoforms Selectively Contribute to Bronchial Epithelial Phenotype.
Am J Respir Cell Mol Biol. 2014 Dec 9;
Authors: Portelli MA, Stewart CE, Hall IP, Brightling CE, Sayers I
Abstract
The urokinase plasminogen activator receptor (uPAR) gene (PLAUR) has been identified as an asthma susceptibility gene, with polymorphisms within that gene being associated with baseline lung function, lung function decline and lung function in a smoking population. Soluble cleaved uPAR (scuPAR), a molecule identified as a marker of increased morbidity and mortality in a number of diseases, has itself been shown to be elevated in the airways of asthma and COPD patients. However, the functionality of soluble receptor isoforms and their relationship with an important initiator for obstructive lung disease, cigarette smoke, remains undefined. In this study, we set out to determine the effect of cigarette smoke on soluble uPAR isoforms, its regulatory pathway and the resultant effect on bronchial epithelial cell function. We identified a positive association between cigarette pack/years and uPAR expression in the airway bronchial epithelium of biopsies from asthma patients (n=27, P=0.0485). In vitro, cigarette smoke promoted cleavage of uPAR from the surface of bronchial epithelial cells (1.5X induction, P<0.0001) and induced the soluble spliced isoform through changes in mRNA expression (~2X change, P<0.001), driven by loss of endogenous 3`UTR suppression. Elevated expression of the soluble isoforms resulted in a pro-remodelling cell phenotype, characterised by increased proliferation and MMP-9 expression in primary bronchial epithelial cells. This suggests that cigarette smoke elevates soluble receptor isoforms in bronchial epithelial cells through direct (cleavage), and indirect (mRNA expression) means. These findings provide further insight into how cigarette smoke may influence changes in the airways of importance to airway remodelling and obstructive lung disease progression.
PMID: 25490122 [PubMed – as supplied by publisher]
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