# Mechanism for Hypertonic Saline Effect on Mucociliary Transport

> **NIH NIH R56** · UNIVERSITY OF IOWA · 2020 · $465,181

## Abstract

PROJECT SUMMARY/ABSTRACT
Cystic fibrosis (CF) remains a life-threatening disorder caused by inherited mutations in the cystic fibrosis
transmembrane conductance regulator (CFTR) gene. In CF airways, impaired mucus clearance set up an
environment prone to chronic bacterial infections, prominent neutrophilic inflammation, remodeling, and
progressive loss of lung function. Early interventions that enhance mucus clearance and prevent mucus
accumulation could dramatically change the outcome of CF lung disease. The lack of an animal model and a
sensitive mucus clearance prevented understanding of early CF lung disease pathogenesis. Two novel
milestones made this possible: 1) CF pig, a model that develops the hallmarks of human CF airway disease.
2) CT-based MCT, a sensitive computed-tomography (CT) based mucus clearance assay with high spatial and
temporal resolution. We found that in CF pigs, MCT is impaired after cholinergic stimulation. We identified
failed detachment of mucus strands from CF submucosal gland (SMG) ducts impaired mucus clearance.
Hypertonic saline (HS) is widely used to improve mucus clearance. However, its use is limited by unwanted
side-effects and mixed efficacy in CF. A better understanding of the mechanism of HS on mucus clearance
will advance development of therapeutic strategies. HS is supposed to enhance mucus clearance in several
putative mechanisms; by increasing ASL height, by stimulating SMG secretions, by disrupting ionic
interactions, or by altering ciliary beat frequency. Our novel mucus clearance assay will provide a framework
to investigate these mechanisms. The overarching goal of this project is to understand the mechanisms of
mucus transport in the airways. The project addresses two main questions. First, how does HS increase
mucus clearance under basal condition? By blocking the cholinergic response with atropine and examining the
effects in vivo and ex vivo will elucidate the mechanism. Investigating in CF will suggest whether HS have
unintended potentially adverse effects and whether these adverse effects could be blocked by atropine.
Second, does HS alone or in combination with a reducing agent (TCEP) enhance mucus clearance in CF after
cholinergic stimulation? Here, in contrast to the prior question, submucosal gland secretion will be stimulated
prior to delivering HS. Answers will indicate whether HS increases mucus clearance by disrupting the ionic
interactions that hold mucus together, or by increasing ASL height. Combining HS with a reducing agent that
can disrupt mucus disulfide interactions, will suggest whether the effect is additive or not. This research will
allow us to better understand the mechanism of HS effect on mucus clearance. Whether HS might work
through stimulation of submucosal glands or osmotically increasing ASL height should make inroads to
develop new therapies.

## Key facts

- **NIH application ID:** 10241746
- **Project number:** 1R56HL147073-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Mahmoud Abou Alaiwa
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $465,181
- **Award type:** 1
- **Project period:** 2020-09-17 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241746

## Citation

> US National Institutes of Health, RePORTER application 10241746, Mechanism for Hypertonic Saline Effect on Mucociliary Transport (1R56HL147073-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10241746. Licensed CC0.

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