Journal of Allergy and Clinical Immunology
Effects on Lung-cell PhysiologyEffects of β-agonists on airway epithelial cells☆,☆☆
Section snippets
Expression of βAR on the airway epithelium
The first step in understanding airway epithelial cell responses to β-agonists was to evaluate which cells in the superficial airway epithelium and in submucosal glands express βARs. Several approaches were used for this purpose. Application of radiolabeled β-agonists and antagonists to detect βARs by autoradiography in human lung revealed that the superficial epithelium expresses mainly βARs and that β1ARs and β2ARs coexist on submucosal gland cells.1, 2 Another approach, the use of in situ
β-Agonists and ciliary beat frequency
Ciliary beating is an integral part of the mucociliary transport apparatus, and it has been well established that β-agonists stimulate ciliary beat frequency (CBF) in a variety of mammalian airway epithelial cells. β-Agonists used in these studies included isoproterenol,11, 12, 13, 14, 15, 16, 17, 18, 19 fenoterol,20, 21, 22 albuterol,7, 23, 24 BRL 37344 (a β3-agonist),7 and salmeterol.23
The main mechanism by which these β-agonists increase ciliary beating is through stimulation of adenylyl
β-Agonists and mucus secretion
The majority of data on mucus secretion in response to β-agonists stems from the 1980s, and whether human airways secrete mucus upon β-agonist stimulation is controversial. In keeping with the data on receptor expression4 and the data on morphometric evaluation after stimulation,39, 40 β-agonists cause degranulation of mainly mucous cells in the submucosal glands in the cat and ferret. These findings may explain why relatively thick secretions are produced in cat trachea after β-agonist
β-Agonists and ion transport
Proper water and ion transport across the airway epithelium are critically important to maintain an adequate airway surface liquid layer and effective mucociliary clearance. Despite this fact and current intense investigations, no definite consensus has been reached on the physiology of the airway surface liquid layer with respect to production, regulation, and composition. Two competing theories have been developed, the isotonic model and the hypotonic model, with many arguments seeming to
β-Agonists and epithelial protection
Bacteria, including Pseudomonas aeruginosa, have been shown to release proteases that cause human nasal epithelial disruption as well as CBF slowing in vitro.54 The release of bacterial products such as hydroxy-phenazine, pyocyanin, and a rhamnolipid has also been shown to decrease CBF,55, 56, 57, 58 as well as to decrease mucus transport velocity.59, 60 The mechanism of pyocyanin-induced ciliary inhibition has been studied in detail, and two mechanisms have been implicated: direct action of
β-Agonists and epithelial reaction to inflammatory stimuli
Airway epithelial cells are capable of releasing a variety of inflammatory mediators, including prostaglandins, 15-lipoxygenase products, cytokines (eg, IL-6, IL-8, GM-CSF, and TNF-α), and nitric oxide. The cells are also capable of up-regulating the expression of adhesion molecules, including intercellular cell adhesion molecule-1 (ICAM-1), in response to inflammatory stimuli. Recent investigations have examined the influence of β-agonists on stimulated cytokine release and ICAM-1 expression.
β-Agonists and epithelial wound repair
cAMP and PKA have been implicated in cell migration and wound repair. In bovine bronchial epithelial cells, isoproterenol increased the migration of cells to speed up the closure of mechanically and enzymatically induced wounds of submerged monolayers.70 The signaling pathway responsible for this response was found to go through cAMP and subsequently PKA, which in turn inhibited Rho. These findings, although not confirmed in clinical trials, may have important implications for patients with
Conclusions
β-Agonists exert a variety of effects on airway epithelial cells. They clearly increase CBF, and the mechanism of this increase has been studied in detail. The increase in CBF is likely the main mechanism by which these agonists increase mucociliary clearance in vivo. Effects on mucin secretion are likely subtle in human airways and possibly clinically irrelevant. Other effects of β-agonists on airway epithelial cells are less well studied and some remain controversial. Thus, we are left with
Acknowledgements
I thank Drs Richard J. Bookman, Gregory E. Conner, Rosanna Forteza, and Adam Wanner for their valuable comments and support over many years.
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Supported by grants from the National Institutes of Health.
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Reprint requests: Matthias Salathe, MD, Division of Pulmonary and Critical Care Medicine (R-47), University of Miami School of Medicine, 1600 NW 10th Ave, RMSB 7063, Miami, FL 33136.