The failure to understand the pathogenesis of CF lung disease reflects, in part, our ignorance of the normal physiology of airway surface liquids (ASL). Project I proposes experiments designed to distinguish between two competing theories that purport to describe the normal physiology of ASL and measure the transport technologies interfaced with experiments using novel cell culture preparations.
Specific Aim 1 sill utilize large and small airway cultures and confocal microscopy to study the physiology and ASL at the microscopic level. Key questions will focus on delineating whether there are distinct mucus and periciliary liquid layers with ASL, and whether water (PCL) moves axially toward the mouth up airways surfaces or not.
Specific Aim 2 focuses on characterizing and interrelation functions of small with large airway epithelia. A comprehensive analysis of expression of genes relevant to salt secretion and absorption will be performed to test for potential regional and intra-regional patterns of absorption (proximal airways) versus secretion (glands, ?distal bronchioles). Planar and novel biofiber preparations populated with epithelia derived from microdissected bronchioles and large airways will be characterized with respect to routes of ion permeation, water permeability (L/p), volume absorption (J/v), and surface liquid ion composition. Selected parameters from the cultured preparations will be compared to data derived from freshly excised preparations. Finally, Specific Aim 3 will measure the effects of mutations in CFTR on these functions. Routes of ion permeation, L/p, and J/v will be measured in culture preparations from CF large and, if possible, small airways. A primary goal will be to measure the two parameters that discriminate between the competing theories: (1) ASL composition; and (2) existence of/ rates os isotonic J/v and its relationship to effective mucus clearance. Thus, this project should develop novel information integrating local and intra-regional ASL metabolism in health and develop key information regarding CF-specific defects in these functions that promote infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL060280-02
Application #
6202585
Study Section
Project Start
1999-09-01
Project End
2000-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Livraghi-Butrico, Alessandra; Grubb, Barbara R; Wilkinson, Kristen J et al. (2017) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol 10:395-407
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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Livraghi-Butrico, Alessandra; Kelly, Elizabeth J; Wilkinson, Kristen J et al. (2013) Loss of Cftr function exacerbates the phenotype of Na(+) hyperabsorption in murine airways. Am J Physiol Lung Cell Mol Physiol 304:L469-80
Graeber, Simon Y; Zhou-Suckow, Zhe; Schatterny, Jolanthe et al. (2013) Hypertonic saline is effective in the prevention and treatment of mucus obstruction, but not airway inflammation, in mice with chronic obstructive lung disease. Am J Respir Cell Mol Biol 49:410-7
Livraghi-Butrico, A; Kelly, E J; Klem, E R et al. (2012) Mucus clearance, MyD88-dependent and MyD88-independent immunity modulate lung susceptibility to spontaneous bacterial infection and inflammation. Mucosal Immunol 5:397-408
Kreda, Silvia M; Davis, C William; Rose, Mary Callaghan (2012) CFTR, mucins, and mucus obstruction in cystic fibrosis. Cold Spring Harb Perspect Med 2:a009589

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