The Proceedings of the American Thoracic Society 1:2-3 (2004)
© 2004 The American Thoracic Society
Chairman's Summary
Richard C. Boucher
Correspondence and requests for reprints should be addressed to Richard C. Boucher, M.D., University of North Carolina at Chapel Hill, Cystic Fibrosis/Pulmonary Research & Treatment Center, CB# 7248, 7011 Thurston Bowles, Chapel Hill, NC 27599-7248. E-mail: rboucher{at}med.unc.edu
The mechanical clearance of mucus from airway surfaces constitutes the primary form of innate airways defense. This clearance requires the activities of ion transport systems located within the airway epithelium, secreted soluble products—particularly mucins that organize into a mucus layer—and the vectorial activities of ciliary beating. The concept of this conference was to examine the integration of the activities that mediate this complex clearance process in health and disease.
The first session concentrated on the elucidation of the molecular identity, biophysical properties, and regulation of the major apical membrane ion channels that mediate airway epithelial ion transport. As shown in Figure 1
, the epithelial Na+ channel (ENaC) is expressed at the apical membrane of airway epithelia and is rate-limiting in controlling the rate of transepithelial Na+ and volume absorption. Also, in the apical membrane of airway epithelia are two Cl- channels. The cystic fibrosis transport regulator (CFTR) Cl- channel is regulated by cAMP-dependent and protein kinase C–dependent mechanisms and may be the channel that confers the tonic (basal) Cl- conductance to airway epithelia. The Ca2+-activated Cl- channel (CaCC) has been identified as an important channel that responds acutely to stimuli at the apical membrane of airway epithelia and appears to be molecularly distinct from CFTR.
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Figure 1. Schema showing the three apical membrane ion channels that mediate the rate and direction (absorption versus secretion) of ion transport across normal airway epithelia. The epithelial Na+ channel (ENaC), cystic fibrosis transmembrane regulator (CFTR), and Ca2+-activated Cl- channel (CaCC) are depicted. PCL = periciliary liquid.
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The second session focused on the manner in which these channels respond to local stimuli in the airway surface liquid environment. As shown in Figure 2
, complex protein–protein interactions organize receptors that may act as "sensors" to environmental influences on the airway surface liquid (e.g., the adenosine A2b receptor) and transfer information across the apical membrane to enzymes that generate signals (e.g., adenylate cyclase) that regulate in a very local fashion the activity of CFTR. Interestingly, the entire complex of CFTR activators (e.g., cAMP-dependent protein kinase A) and inactivators (e.g., phosphodiesterases) may be present in this domain. Further, a complex regulatory interrelationship between CFTR and ENaC has been demonstrated functionally (i.e., CFTR appears to have a tonic inhibitory effect on ENaC activity). However, at present, no regulatory mechanism that links these two channels together has been identified.
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Figure 2. Network of proteins in apical membrane of airway epithelia that may link CFTR and ENaC in a regulatory relationship with themselves and the actin cytoskeleton.
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The third session integrated macromolecules into the airway surface environment. Mucins are large macromolecules secreted from goblet cells in the superficial epithelium and mucus cells in the gland to form the mucus layer. The concept has emerged that mucins are secreted "dry" from mucin-secreting cells and are hydrated by the water in the surface environment. Thus, the formation of the mucus layer appears to require an adequate volume of liquid on airway surfaces. How coordination is achieved between mucin secretion rates and salt and water transport rates across airway surfaces is currently unknown. However, experimental evidence suggests that when mucins constitute roughly 1.5% of the percent solids content of the airway surface liquid, an adequately hydrated and hence transportable mucus layer is formed.
Finally, a unifying mechanism that may account for mucus retention in the lung and a propensity to infection has emerged from studies of the normal physiology of mucin and liquid secretion and how they may be deranged in CF (Figure 3)
. For example, in CF an ion transport–mediated hyperabsorption of airway surface liquid volume leads to a depletion of the periciliary liquid layer/lubricant layer that produces adhesion of thickened mucus to cell surfaces. In chronic bronchitis, it appears that an increase in the rate of mucin secretion "soaks up" the periciliary liquid layer and promotes adhesion. These studies have led to the concept that therapeutic agents that restore the hydration status of airway surfaces may prove to be beneficial for patients with cystic fibrosis or chronic bronchitis by "flushing" mucus from airway surfaces and restoring mucus clearance.
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Figure 3. Airway surface liquid volume in health and disease. Left: In health, there is sufficient airway surface liquid to generate a discrete periciliary liquid (PCL) and a well hydrated mucus layer. Right: In infectious airways disease, a reduced airway surface liquid volume leads to PCL depletion, increased mucin concentration in the mucus layer, and adhesion of the mucus layer to the cell surface.
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The articles in this issue are designed to lead the reader through the sequence described in these figures by providing real data. The articles and speculations are meant to emphasize important concepts and identify important areas that are in need of future research. Thus, we hope that this volume can serve as a framework for novel concepts to be applied to the pathogenesis and therapy of airways diseases associated with mucus retention and infection.
(Received in original form June 19, 2003; accepted in final form September 24, 2003)
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