Characterizing the airway epithelium following chemical exposure: molecular alterations and their potential utility in the treatment of lung disease
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The human body encounters a number of chemical exposures on a daily basis, which may have short- or long-term health implications. Previously it has been demonstrated that the entire respiratory tract of an individual reacts to exposures like tobacco smoke in a similar manner, and that common molecular changes can be measured in airway epithelium. I propose that cataloguing the exposure of airway epithelial cells to tobacco cigarette (TCIG) smoke and its constituents, electronic cigarette (ECIG) aerosol and other drugs and small molecules can significantly increase the understanding of chemical exposure and identify common gene expression alterations. First, I determined the molecular impact of ECIG aerosol exposure on human airway epithelium in vitro, including alterations in genes related to xenobiotic metabolism, oxidative stress, and ciliated cells. These changes were generally less pronounced than the effects of TCIG exposure, and were more pronounced in ECIG products containing nicotine than those without nicotine. Furthermore, gene expression differences observed in vitro were concordant with differences observed in airway epithelium collected from ECIG users. Second, I examined the impact of TCIG exposure and TCIG constituents on premalignant airway cells, to better understand the progression or regression of precancerous lesions. These data could also identify the constituents of TCIGs and the precancerous mutations that increase the risk for malignancy. Third, in an effort to build a high-throughput methodology for chemical exposures, I exposed primary lung cell lines to small molecule therapeutics and identified lung-specific and lung cell-type-specific effects of exposure, suggesting that profiling additional cell lines would further inform airway gene expression in response to exposure and that organ-specific exposure profiling may provide valuable insight into drug discovery for common diseases. Overall, transcriptomic profiles from the airway epithelium reflect exposure to various inhaled and chemical perturbations. These gene expression profiles indicate common changes across a multitude of airway exposures as well as unique alterations specific to a given perturbation. Gene expression profiling can therefore be used to detail the potential response to a compendium of chemical exposures including those that are either well-established or potential risk factors for chronic lung diseases.