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. Bacterialand 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), colonizationby bacteria and frequent exacerbations of disease related to MCC failure. The CFTR-induced anomalies inASL solute concentration and subsequent ASL dehydration are a central cause of CF lung disease. Clinicalsimilarities between COPD and Cystic Fibrosis (CF) suggest that despite differences in pathogenesis, thereare key similarities in their pathophysiology. Adenosine and purinergic control of airway hydration are likelyimportant in both diseases, as we have observed that (like CF) COPD patients also have decreased ASLdehydration and adenosine levels relative to normal volunteers. The overarching hypothesis of this project isthat smoking predisposes to decreased MCC due to ASL dehydration, partly due to decreased ASLadenosine and diminished innate host defense. In Project IV, we will test the hypothesis that smokers havedecreased MCC with alterations in purine and adenosine biology by comparing these airway processesbetween normal volunteers and smokers. We also hypothesize that smoking will cause decreasedmacrophage function and bacterial colonization of the airway. We will compare our results in normalvolunteers and smokers to those from similarly studied COPD (Project V) and CF (Project VI) patients, as wesuspect that smoking-induced changes will mimic those in COPD. We will also examine MCC, hydration andairway responses in normal volunteers and smokers after challenge with inhaled endotoxin (a bacterialproduct found in tobacco smoke) and experimental viral infection to determine if MCC in smokers is lessadaptive to these challenges.
These aims will provide novel in vivo data on smoking-induced airwaypathophysiology in humans. The medical significance of these studies is that they will firmly establish theimportance of mucus clearance to maintain respiratory health and will elucidate disease mechanisms andtherapeutic targets applicable for many chronic obstructive airway diseases.
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