Patients with cystic fibrosis (CF) and chronic bronchitis, i.e. COPD, exhibit a significantly reduced mucus clearance. The overarching goal of this project is to test the hypothesis that reduced rates of mucociliary and cough clearance in these patients are related to mucus dehydration and the resulting increased adhesion of mucus to cells as well as increased mucus cohesion strength. Both CF and COPD subjects exhibit an increase in ainvay mucus concentration, reflecting: 1) reduced ainway surface solvent (salt/water), e.g., as observed with CFTR dysfunction;2) mucin hypersecretion, as observed with goblet cell hyperplasia;or 3) a combination of the two. Based on our recent theoretical and experimental data, we have developed a novel model, referred to as the "two-gel" model, that suggests that in addition to a mucus gel, ain/vays exhibit a "periciliary" layer (PCL), which is also a gel formed by tethered mucins (MUC1, MUC4, and MUC16). Efficient clearance requires hydration of the PCL that is sustained as long as its osmotic pressure is higher than that of the mucus gel layer. Importantly, the osmotic pressure of the mucus layer is largely determined by the concentration of the secreted mucins MUC5AC and MUC5B. To test our two-gel hypothesis, we have developed novel techniques to measure mucus osmotic pressure, adhesion/cohesion strength, viscosity, and elastic modulus and to determine the effect of these physical properties on mucus transport rate for both normal and CF cultures. We propose that reducing mucus concentration, cohesion strength, and mucus adhesion to epithelial cells will restore effective mucus clearance and thus benefit both CF and COPD patients. The novel approach to physical processes in airway surface layer will allow us to identify the optimal combination of rehydration and pharmacological agents to restore/accelerate the rate of mucus clearance. The identified agents that reduce the adhesion/cohesion strength and restore normal mucus clearance will be tested in mouse models of obstructive lung disease (Project II) and in COPD patients (Projects III).

Public Health Relevance

This project focus on the developments and validation of new physical models of airway surface layer and the role of mucus hydration, adhesion and cohesion in controlling mucus clearance. These new ideas lead to systematic developments of new drugs aimed at restoring and maintaining mucus clearance in patients with obstructive lung diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL108808-03
Application #
8686928
Study Section
Special Emphasis Panel (ZHL1-CSR-Q)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$374,451
Indirect Cost
$121,651
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Henderson, Ashley G; Ehre, Camille; Button, Brian et al. (2014) Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure. J Clin Invest 124:3047-60
Esther Jr, Charles R; Boucher, Richard C; Johnson, M Ross et al. (2014) Airway drug pharmacokinetics via analysis of exhaled breath condensate. Pulm Pharmacol Ther 27:76-82
Donnelley, Martin; Morgan, Kaye S; Siu, Karen K W et al. (2014) Non-invasive airway health assessment: synchrotron imaging reveals effects of rehydrating treatments on mucociliary transit in-vivo. Sci Rep 4:3689
Liu, Kun; Lukach, Ariella; Sugikawa, Kouta et al. (2014) Copolymerization of metal nanoparticles: a route to colloidal plasmonic copolymers. Angew Chem Int Ed Engl 53:2648-53
Hill, David B; Vasquez, Paula A; Mellnik, John et al. (2014) A biophysical basis for mucus solids concentration as a candidate biomarker for airways disease. PLoS One 9:e87681
Schwab, Ute; Abdullah, Lubna H; Perlmutt, Olivia S et al. (2014) Localization of Burkholderia cepacia complex bacteria in cystic fibrosis lungs and interactions with Pseudomonas aeruginosa in hypoxic mucus. Infect Immun 82:4729-45
Chhetri, Raghav K; Blackmon, Richard L; Wu, Wei-Chen et al. (2014) Probing biological nanotopology via diffusion of weakly constrained plasmonic nanorods with optical coherence tomography. Proc Natl Acad Sci U S A 111:E4289-97
Roy, Michelle G; Livraghi-Butrico, Alessandra; Fletcher, Ashley A et al. (2014) Muc5b is required for airway defence. Nature 505:412-6
Stukalin, Evgeny B; Cai, Li-Heng; Kumar, N Arun et al. (2013) Self-Healing of Unentangled Polymer Networks with Reversible Bonds. Macromolecules 46:
Button, Brian; Okada, Seiko F; Frederick, Charles Brandon et al. (2013) Mechanosensitive ATP release maintains proper mucus hydration of airways. Sci Signal 6:ra46

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