Healthy smokers (without COPD) have increased occurrence of airway infections compared to non-smokers,? and smoking is also the major risk factor for COPD. COPD is characterized by chronic airway obstruction,? decreased mucociliary clearance (MCC), mucus hypersecretion, and chronic airway inflammation. Bacterial? and viral infections are the leading causes of acute exacerbations of COPD. . In Cystic Fibrosis (CF),? dehydration of the airway surface liquid (ASL) leads to decreased mucociliary clearance (MCC), colonization? by bacteria and frequent exacerbations of disease related to MCC failure. The CFTR-induced anomalies in? ASL solute concentration and subsequent ASL dehydration are a central cause of CF lung disease. Clinical? similarities between COPD and Cystic Fibrosis (CF) suggest that despite differences in pathogenesis, there? are key similarities in their pathophysiology. Adenosine and purinergic control of airway hydration are likely? important in both diseases, as we have observed that (like CF) COPD patients also have decreased ASL? dehydration and adenosine levels relative to normal volunteers. The overarching hypothesis of this project is? that smoking predisposes to decreased MCC due to ASL dehydration, partly due to decreased ASL? adenosine and diminished innate host defense. In Project IV, we will test the hypothesis that smokers have? decreased MCC with alterations in purine and adenosine biology by comparing these airway processes? between normal volunteers and smokers. We also hypothesize that smoking will cause decreased? macrophage function and bacterial colonization of the airway. We will compare our results in normal? volunteers and smokers to those from similarly studied COPD (Project V) and CF (Project VI) patients, as we? suspect that smoking-induced changes will mimic those in COPD. We will also examine MCC, hydration and? airway responses in normal volunteers and smokers after challenge with inhaled endotoxin (a bacterial? product found in tobacco smoke) and experimental viral infection to determine if MCC in smokers is less? adaptive to these challenges.
These aims will provide novel in vivo data on smoking-induced airway? pathophysiology in humans. The medical significance of these studies is that they will firmly establish the? importance of mucus clearance to maintain respiratory health and will elucidate disease mechanisms and? therapeutic targets applicable for many chronic obstructive airway diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL084934-03
Application #
7658074
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$619,582
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Muhlebach, Marianne S; Hatch, Joseph E; Einarsson, Gisli G et al. (2018) Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: a multisite study. Eur Respir J 52:
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
Martin, Elizabeth M; Clapp, Phillip W; Rebuli, Meghan E et al. (2016) E-cigarette use results in suppression of immune and inflammatory-response genes in nasal epithelial cells similar to cigarette smoke. Am J Physiol Lung Cell Mol Physiol 311:L135-44
Button, Brian; Anderson, Wayne H; Boucher, Richard C (2016) Mucus Hyperconcentration as a Unifying Aspect of the Chronic Bronchitic Phenotype. Ann Am Thorac Soc 13 Suppl 2:S156-62
Sesma, Juliana I; Weitzer, Clarissa D; Livraghi-Butrico, Alessandra et al. (2016) UDP-glucose promotes neutrophil recruitment in the lung. Purinergic Signal 12:627-635
Sherrard, Laura J; McGrath, Stef J; McIlreavey, Leanne et al. (2016) Production of extended-spectrum ?-lactamases and the potential indirect pathogenic role of Prevotella isolates from the cystic fibrosis respiratory microbiota. Int J Antimicrob Agents 47:140-5
Davis, Stephanie D; Ratjen, Felix; Brumback, Lyndia C et al. (2016) Infant lung function tests as endpoints in the ISIS multicenter clinical trial in cystic fibrosis. J Cyst Fibros 15:386-91
Bennett, William D; Xie, Miao; Zeman, Kirby et al. (2015) Heterogeneity of Particle Deposition by Pixel Analysis of 2D Gamma Scintigraphy Images. J Aerosol Med Pulm Drug Deliv 28:211-8

Showing the most recent 10 out of 60 publications