The goal of this proposal is to develop physical understanding of and therapies for the failure of mucus clearance in patients with chronic bronchitic (CB) diseases, where mucus becomes sticky and adheres to the epithelial cell surface periciliary layer (PCL). We hypothesize that a unifying feature of CB diseases is dehydration of mucus that reflects common elements of pathogenesis in both genetic (e.g., cystic fibrosis) and environmental (e.g., cigarette smoke-induced) forms of CB. We hypothesize that the failure of CB mucus clearance is due to the higher adhesion and cohesion strengths between CB mucus and PCL that reflects mucus dehydration. In Sp.
Aim 1, we will develop experiments, such as peel tests and cavitation rheology technique (CRT) in cultured cell preparations, which would allow us for the first time to measure the adhesion strength between mucus and PCL, the cohesion strength of mucus at different mucus concentrations, and crack propagation rates. Both the adhesion and cohesion strength will be quantified systematically and related to the viscoelastic properties of mucus in corresponding conditions. In Sp.
Aim 2, we will measure mucus adhesion and cohesion in freshly excised ainways from human subjects with cigarette smoke-induced CB and CF, and compare data with cell culture model data. We will also test the relevance of a mouse model of airways mucus adhesion, the pENaC transgenic mouse, to human diseases. In Sp.
Aim 3, we will test combinations of """"""""hydrating"""""""" and mucolytic agents for therapeutic activity in CB subjects.
This Aim will progress single agents/combinations from in vitro testing in cultured cells, using peel test and CRT measurements, to combination therapies in acute and 2 week in vivo testing in the (3ENaC mouse model. The overall goal of the project is to have a novel combination therapy identified for clinical testing in CB subjects within 2 years.

Public Health Relevance

(See Instructions): Chronic bronchitis (CB) is caused by both genetic and environmental factors and affects more than 14 million Americans. Currently, there is little knowledge about the mechanism/or treatment ofthe abnormal airway sections that adhere to ainway surfaces in CB. We propose to utilize novel concepts from polymer physics and methodologies from material sciences to develop much needed effective therapies for CB.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL107168-02
Application #
8262684
Study Section
Special Emphasis Panel (ZHL1-CSR-D (F1))
Program Officer
Punturieri, Antonello
Project Start
2011-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$442,662
Indirect Cost
$142,662
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Livraghi-Butrico, A; Grubb, B R; Wilkinson, K J et al. (2016) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol :
Yu, Dongfang; Davis, Richard M; Aita, Megumi et al. (2016) Characterization of Rat Meibomian Gland Ion and Fluid Transport. Invest Ophthalmol Vis Sci 57:2328-43
Saini, Yogesh; Wilkinson, Kristen J; Terrell, Kristy A et al. (2016) Neonatal Pulmonary Macrophage Depletion Coupled to Defective Mucus Clearance Increases Susceptibility to Pneumonia and Alters Pulmonary Immune Responses. Am J Respir Cell Mol Biol 54:210-21
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Cai, Li-Heng; Kodger, Thomas E; Guerra, Rodrigo E et al. (2015) Soft Poly(dimethylsiloxane) Elastomers from Architecture-Driven Entanglement Free Design. Adv Mater 27:5132-40
Bharti, Bhuvnesh; Fameau, Anne-Laure; Rubinstein, Michael et al. (2015) Nanocapillarity-mediated magnetic assembly of nanoparticles into ultraflexible filaments and reconfigurable networks. Nat Mater 14:1104-9
Hemp, Sean T; Smith, Adam E; Bunyard, W Clayton et al. (2014) RAFT polymerization of temperature- and salt-responsive block copolymers as reversible hydrogels. Polymer (Guildf) 55:2325-2331
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
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
Saini, Yogesh; Dang, Hong; Livraghi-Butrico, Alessandra et al. (2014) Gene expression in whole lung and pulmonary macrophages reflects the dynamic pathology associated with airway surface dehydration. BMC Genomics 15:726

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