The use of aerosolized nicotine products, mostly electronic nicotine delivery systems (ENDS), are growing in popularity and especially among younger individuals who have not necessarily used tobacco products previously. We know little about the impact this has on their future health landscape. Challenges to our understanding of the unique concerns ENDS present to health include their highly variable and inconsistent formulations. Despite this variability, ENDS share in common the delivery of the biologically active component nicotine, which is present in relatively high purity and concentration. This proposal will focus on examining the biologic effects of nicotine that are unique to delivery by aerosolization (aeroNic) and inhalation. Our group has studied the impact of nicotine on both peripheral immune and central processes leading to addiction since the original cloning of the nicotinic acetylcholine receptors (nAChR). Because the effects of nicotine are highly dependent upon its route of delivery, we have first developed a reliable method of aeroNic administration to the mouse that produces quantitative uptake and kinetics comparable to those in humans. The experimental focus will apply this AeroNic delivery system to define its impact on mouse inflammatory stasis in the lung and gastrointestinal (GI) tract, and determine how this modifies the inflammatory response to challenge of the lung by either acute lung injury (ALI) or to allergic eosinophilic inflammation (AEI; a model of asthma). This analysis will be greatly facilitated through application of genetic tools that manipulate signaling through nicotine's principal target in peripheral cells, the nAChRalpha7 (?7). This includes how nicotine couples to specific calcium signaling networks to modulate these pro-inflammatory responses. In preliminary studies, aeroNic actions through ?7 calcium-coupled mechanisms in the lung reduce inflammatory responsiveness and alter epithelial cell signaling networks such as those controlling mucin production. Most recently we have discovered a concurrent and robust impact by aeroNic on microbiota dysbiosis. The experiments proposed build upon these preliminary and published findings to test the project hypothesis: Aerosolized nicotine acts to depress lung responsiveness to ALI and to AEI through modifying ?7 calcium signaling networks controlling normal modulation of immune - epithelial - microbiota interactions. This will be tested in experiments outlined in three interactive Specific aims.
Aim 1 will measure how aeroNic alters the mouse microbiota and if dysbiosis is permanent.
Aim 2 will define transcriptional signaling networks and proteomic mechanisms through which aeroNic acts through ?7 to modify normal epithelial cell function.
Aim 3 will define how aeroNic modifies the lung/GI axis stasis through modifications of mucosal immune cells known to regulate both ALI and AEI. At the conclusion of these experiments we will have a clear understanding of the unique biological impact of aeroNic on the lung and GI and how these changes may modify long-term health outcomes.

Public Health Relevance

Electronic cigarettes (eC) are rapidly increasing in popularity, particularly with younger individuals, yet little is known regarding the impact of inhaled eC vapors into the lung. The common constituent in the many different formulations of eC fluids is nicotine, a biologically active compound known to affect many processes from addiction to inflammation. The purpose of our research is to determine the effects of inhaled aerosolized nicotine on the lung in a mouse model system that will greatly facilitate our understanding of its effects in humans and on their long-term health.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01HL135610-01
Application #
9233646
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Postow, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112