# The role of mucus and pulmonary surface interactions in lung defense

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $388,750

## Abstract

The mucus clearance system of the lung represents a key innate immune system that protects the airway surface
against constant exposure to inhaled infectious and noxious particles. However, abnormal clearance of mucus
by cilia beating and cough represents a significant contributor to the pathogenesis in so-called muco-obstructive
lung diseases, including cystic fibrosis, asthma, and chronic bronchitis. Despite the role that reduced clearance
of mucus plays in patients with muco-obstructive lung diseases, there are large gaps in our knowledge of how
abnormal mucus produces such mucostasis. In order to understand the root causes of the pathology and develop
effective therapies to treat such diseases, it is necessary to understand the fundamental mechanisms involved
in regulating mucus clearance in health and understand how is it affected by disease. Therefore, the goal of this
project is to answer a number of unresolved questions regarding the mucus clearance system. In the first specific
aim, we seek to understand what role airway mucins, the large biopolymers which give mucus its gel-like
properties, play in facilitating efficient mucus clearance in health. Here, we will use novel in vitro cilia- and cough-
mediated clearance assays to test the hypothesis that airway mucins are vital for efficient mucus clearance out
of the lung, as a result of interactions between mucins and the airway cell surface. Studies will also identify which
mucin domains are involved in this interaction. In the second aim, we will address another outstanding question
of whether higher-order multimerization of mucins, to very long polymers, is required for efficient mucus transport.
This question has clinical relevance as disulfide bond reducing agents, which “cleave” long-chain mucins and
reduce the elastic properties of mucus, have been proposed as a mucolytic therapy for lung diseases. In this
aim, we will test the hypothesis that mucin polymerization is required for efficient cilia- and cough-mediated
mucus transport by facilitating the clearance of mucus transport across regions of the airways with poor cilia beat
coordination or devoid of ciliated cells, as a result of airway damage associated with gastric aspiration, cigarette
smoking, and certain viral infections. In the third aim, we will test the hypothesis that mucin/cell surface
interactions are abnormal in diseases associated with hyperproduction of secreted MUC5AC mucin, as a result
of Th2 cytokine signaling. Specifically, we will test the hypothesis that chronic IL-13-mediated increases in
MUC5AC expression can increase the strength of the cilia-mucus interactions, generating a more adherent, hard
to clear, mucus layer. To assess the impact of disease-related increases in MUC5AC expression we will utilize
novel mucus adhesion and friction testing devices which quantifies the adherence of mucus to the airway surface
and resistance of mucus propulsion. The testing of these hypotheses will be critical to addre...

## Key facts

- **NIH application ID:** 10051643
- **Project number:** 2R01HL125280-05A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** BRIAN M BUTTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,750
- **Award type:** 2
- **Project period:** 2015-07-03 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051643

## Citation

> US National Institutes of Health, RePORTER application 10051643, The role of mucus and pulmonary surface interactions in lung defense (2R01HL125280-05A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10051643. Licensed CC0.

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