The long-term goal of this project is to better define the role of normal airway epithelial ion (and water) transport in lung defense, and identify the primary (and other early) pathogenic events in CF lung disease. The overall hypothesis of this proposal is that the surface epithelia in normal airways exhibit """"""""isotonic volume absorption"""""""", and the primary pathophysiologic event in CF lung disease involves accelerated absorption of isotonic liquid, which limits the normal hydration of mucus in conduct airways. Mucus stasis ensures, with impaction in small airways and predisposition to chronic bacterial infection. We will specifically address an alternative hypothesis, which suggests that normal airways absorb ions, but not volume, and generate a hypotonic airway surface liquid (ASL). Under the """"""""hypotonic ASL"""""""" paradigm, the pathogenesis in CF airways is similar to that of the sweat duct, i.e., an inability to absorb NaCl, which results in higher concentrations of salt relative to normal, and inhibition of salt-sensitive small-peptide anti-microbial activities. We will use specific techniques in vivo, including ion-selective electrodes, to study and lower airway epithelial function and ASL composition. We will study normal subjects, CF patients (including infants and neonates), and pertinent disease-control groups, including patients with pseudohypoaldosteronism (PHA) and Sjogren's syndrome. These studies are designed to define the relative contribution of surface epithelia and SMGs to ASL metabolism, in part to test theories related to SMG dysfunction in the pathogenesis of CF airway disease. We will measure the water content (percent solids) of airway secretions in CF and normals to test the hypothesis that accelerated isotonic volume absorption leads to reduced hydration of mucus in CF. Pertinent data will also be generated that address the role of specific inflammatory or neutrophil functions in early pathogenesis. Finally, studies of BAL in CF infants and neonates will directly test whether mucus obstruction precedes infection, or whether infection occurs first.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
1P50HL060280-01
Application #
6110935
Study Section
Project Start
1998-09-01
Project End
1999-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
1
Fiscal Year
1998
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
Chen, Gang; Volmer, Allison S; Wilkinson, Kristen J et al. (2018) Role of Spdef in the Regulation of Muc5b Expression in the Airways of Naive and Mucoobstructed Mice. Am J Respir Cell Mol Biol 59:383-396
Livraghi-Butrico, A; Grubb, B R; Wilkinson, K J et al. (2017) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol 10:829
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
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
Mellnik, John; Vasquez, Paula A; McKinley, Scott A et al. (2014) Micro-heterogeneity metrics for diffusion in soft matter. Soft Matter 10:7781-96
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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