Cigarette Smoke Induces uPAR in Vivo and Isoforms Selectively Contribute to Bronchial Epithelial Phenotype.

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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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Ozone and cigarette smoke worse for asthma than smoke alone – Los Angeles Times

Ozone and cigarette smoke worse for asthma than smoke alone

The LA Times is reporting that Ozone generators are often used in hotel rooms, cars and private homes to get rid of the smell of cigarette smoke, but new evidence suggests that this cure may be worse than the disease. Researchers at the Univeristy of California’s Lawrence Berkeley National Laboratory have found that ozone combines with nicotine and other components of cigarette smoke to produce chemicals that are a greater asthma hazard than the original smoke. In particular, the chemicals combine to form ultrafine aerosols that can carry dangerous chemicals deep into the lungs, where they trigger the development of asthma.

Environmental chemist Mohamad Sleiman and his colleagues used the Advanced Light Source at the laboratory to monitor the interaction of ozone with nicotine and other components of cigarette smoke. They reported in the journal Atmospheric Environment that, to their surprise, the chemicals reacted to form the ultrafine aerosols — smaller than those generated by smoking itself, and thus able to penetrate more deeply into the lungs. They also generated toxic compounds with a strong potential to stimualte asthma.

“The results predict that exposure to these ultrafine particles containing many oxidized species with high ‘Asthma Hazard Indices’ may increase the risks of asthma,” Sleiman said in a statement. “Formation of ultrafine particles appears to be a key dynamic step in the transformation of secondhand smoke to thirdhand smoke.”

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The Berkeley group had reported earlier this year that smoking can deposit nicotine and other products on furniture and other surfaces, where it can be released over long periods of time. This so-called thirdhand smoke constitutes a previously unsuspected source of exposure to carcinogenic and asthma-inducing chemicals. Attempting to removethe residue with ozone — which was thought to react with the chemicals and destroy them — can apparently create even more hazardous compounds, the researchers found.

The study was funded by the Tobacco-Related Disease Research Program of the University of California Office of the President.