# The effect of Inhaled Nicotine on Pulmonary Surfaces

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $456,000

## Abstract

Nicotine is the pharmacologically active/addictive compound in tobacco. As such, the lung serves as an ideal
and efficient delivery route for nicotine absorption into the bloodstream where it can then cross the blood brain
barrier and induce psychotropic effects on the brain. Recently, with the advent of electronic cigarettes (E-
Cigs), people have begun inhaling purified nicotine in a liquid vehicle (typically vegetable glycerin/propylene
glycol). While the effects of nicotine on the brain and cardiovascular system are well known, the effects of
nicotine on the lung have been less studied. Mucus clearance is a major part of the lung's innate defense
system and represents the first point of contact of the body with inhaled nicotine. Perturbations in CFTR-
mediated ion transport, which is required for mucus hydration/clearance, or biochemical alterations to mucins
impair this system, leaving the lung more prone to mucus accumulation/plugging and viral infections, as
evidenced by cystic fibrosis and chronic bronchitis lung disease. Our preliminary data indicate that E-cig users
have a drastically altered mucus proteome which is suggestive of immunosuppression. In vitro, we found that
nicotine, acting through intracellular Ca2+ (i) dephosphorylated CFTR leading to CFTR inactivation and
internalization to the endoplasmic reticulum and (ii) altered mucin rheology by directly interacting with mucins.
Furthermore, our data also suggest that the normal ability of the airways to activate CFTR and secrete mucins
to generate an “airway flush” to remove inhaled viruses is impaired following nicotine exposure, which is
predicted to lead to a failure to resolve common viral infections such as respiratory syncytial virus. We
hypothesize therefore, that nicotine causes an immunosuppressed phenotype that leaves the lung
more prone to viral exacerbations. Specifically, we propose that (i) nicotine-induced Ca2+ signaling leads to
CFTR dephosphorylation and internalization to the endoplasmic reticulum (ii) altered mucus rheology and (iii) a
failure to efficiently resolve viral infections. We shall study this hypothesis with the following specific aims:
Aim 1. To test the hypothesis that nicotine, via increases in intracellular Ca2+, causes CFTR
dephosphorylation and retrograde transport of CFTR to the ER that leads to ASL dehydration.
Aim 2. To assess the impact of nicotine on mucin secretion, mucus/mucin biophysical and barrier
properties, including their integrity, polymeric structure, and maturation.
Aim 3. To determine the impact of inhaled nicotine on outcomes of respiratory virus infection in vivo.

## Key facts

- **NIH application ID:** 9840929
- **Project number:** 5R01HL135642-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Mehmet Kesimer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $456,000
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840929

## Citation

> US National Institutes of Health, RePORTER application 9840929, The effect of Inhaled Nicotine on Pulmonary Surfaces (5R01HL135642-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9840929. Licensed CC0.

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