Electronic Cigarette Vapor with Nicotine Causes Airway Mucociliary Dysfunction Preferentially via TRPA1 Receptors

Abstract

of Health (NIH) -F32-HL140729 (to S.C.) and R01 HL139365 (to M.S.) RUNNING TITLE: Vaped nicotine impairs mucociliary function preferentially via TRPA1 SUBJECT CATEGORY DESCRIPTOR: 6.17 Smoking Health Effects TOTAL WORD COUNT: 3985 AT A GLANCE COMMENTARY: Scientific Knowledge on the Subject E-cigarettes are marketed as safer alternatives to conventional cigarettes due to their defined composition and noncombustible nature. However, it is unclear how exposure to e-cigarette vapor, colloquially referred to as "vape", affects naïve airway epithelia. It is largely unknown to what extent individual constituents of vape, such as nicotine and flavoring agents, influence pulmonary function, if at all. The transient receptor potential ankyrin 1 (TRPA1) is a molecular target for vape effects due to its expression in airway epithelia and its reported gating by nicotine, reactive oxidants, and flavors, especially cinnamaldehyde. What This Study Adds to the FieldThis study implicates nicotine as a key "vape" constituent that acutely impairs airway mucociliary functions in vitro and in vivo (sheep). A functional, nicotine-sensitive TRPA1 receptor is natively expressed in human and sheep bronchial epithelial cells and mediates the effects of nicotine and e-cigarette vapors. Importantly, its inhibition prevents mucociliary dysfunction in vitro and in vivo. These findings implicate TRPA1 as a driver of mucociliary dysfunction induced by nicotine-containing e-cigarette vapor.ABSTRACT RATIONALE: Electronic cigarette (e-cig) use has been widely adopted under the perception of safety. However, possibly adverse effects of e-cig vapor in never-smokers are not well understood. OBJECTIVES:Effects of nicotine-containing e-cig vapors on airway mucociliary function were tested in differentiated human bronchial epithelial cells (HBECs) isolated from never-smokers and in the airways of a novel, ovine large animal model. METHODS:Mucociliary parameters were measured in HBECs and in sheep. Systemic nicotine delivery to sheep was quantified using plasma cotinine levels, measured by ELISA. MEASUREMENTS AND MAIN RESULTS:In vitro, exposure to e-cig vapor reduced airway surface liquid hydration and increased mucus viscosity of HBECs in a nicotinedependent manner. Acute nicotine exposure increased intracellular calcium levels, an effect primarily dependent on transient receptor potential ankyrin 1 (TRPA1). TRPA1 inhibition with A967079 restored nicotine-mediated impairment of mucociliary parameters including mucus transport in vitro. Sheep tracheal mucus velocity (TMV), an in vivo measure of mucociliary clearance, was also reduced by e-cig vapor. Nebulized e-cig liquid containing nicotine also reduced TMV in a dose-dependent manner and elevated plasma cotinine levels. Importantly, nebulized A967079 reversed the effects of e-cig liquid on sheep TMV. CONCLUSIONS:Our findings show that inhalation of e-cig vapor causes airway mucociliary dysfunction in vitro and in vivo. Furthermore, they suggest that the main Page 4 of 64 2 nicotine effect on mucociliary ...

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