Effects of β-agonists on airway epithelial cells

doi:10.1067/mai.2002.129412

Journal of Allergy and Clinical Immunology

Volume 110, Issue 6, Supplement, December 2002, Pages S275-S281

https://doi.org/10.1067/mai.2002.129412 Get rights and content

Abstract

β-Adrenergic receptor (βAR) agonists exert a variety of effects on airway epithelial cells. Among their best known actions is their ability to increase ciliary beat frequency, mediated by cyclic adenosine monophosphate (cAMP) production, stimulation of protein kinase A (PKA), and phosphorylation of an outer dynein arm light chain. Submucosal glands express βARs, and β-agonists may stimulate secretion of mucus from airways, although human data are controversial. β-Agonists may also affect ion transport across epithelial cells by opening apical ion channels such as the cystic fibrosis transmembrane regulator. This effect, likely to occur in submucosal glands, can influence water fluxes across the airway epithelium and may have profound influences on mucus hydration. βAR activation can increase intracellular calcium in some ciliated cells, thereby stimulating ciliary beating and possibly influencing transepithelial ion transport. βAR-mediated activation of cAMP-dependent protein kinase accelerates epithelial cell migration, thereby enhancing epithelial wound repair. β-Agonists reduce the ultrastructural damage seen with infection and potentiate secretion of certain cytokines from epithelial cells while inhibiting secretion of others. Finally, β-agonists may have effects on airway epithelial cells that are mediated through βARs but do not require cAMP production. The signaling mechanisms of some β-agonist effects are not well understood but are important to our understanding of airway epithelial cell growth, differentiation, and function. (J Allergy Clin Immunol 2002;110:S275-81.)

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.

^☆☆: 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.

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Effects on Lung-cell PhysiologyEffects of β-agonists on airway epithelial cells☆,☆☆

Abstract

Section snippets

Expression of βAR on the airway epithelium

β-Agonists and ciliary beat frequency

β-Agonists and mucus secretion

β-Agonists and ion transport

β-Agonists and epithelial protection

β-Agonists and epithelial reaction to inflammatory stimuli

β-Agonists and epithelial wound repair

Conclusions

Acknowledgements

Eur J Pharmacol

Eur J Pharmacol

Life Sci

Jpn J Pharmacol

Eur J Pharmacol

Biochem Biophys Res Commun

Biophys J

Pulm Pharmacol

Tissue Cell

Chest

Pulmonol Pharmacol

Autoradiographic visualization of beta-adrenoceptor subtypes in human lung

Am Rev Respir Dis

Localization of cAMP in dog and cat trachea: effects of β-adrenergic agonists

Am J Physiol

Mapping of adrenergic receptors in the trachea by autoradiography

Exp Lung Res

Expression and function of the β-adrenergic receptor coupled-adenylyl cyclase system on human airway epithelial cells

Am J Respir Crit Care Med

Lack of β3-adrenergic receptor mRNA expression in adipose and other metabolic tissues in the adult human

Mol Pharmacol

Beta-adrenergic receptors and their regulation

Am J Respir Crit Care Med

Mechanism of action of β2-adrenergic agonists

Mechanosensitive and β-adrenergic control of the ciliary beat frequency of mammalian respiratory tract cells in culture

Am Rev Respir Dis

Control of the beat cycle of respiratory tract cilia by Ca2+ and cAMP

Am J Physiol

Beta-adrenergic stimulation of respiratory ciliary activity

J Appl Physiol

Influence of sympathetic and parasympathetic substances in clinical concentrations on human nasal ciliary beat

Rhinology

Effects of pharmaceutical compounds on ciliary beating in human nasal epithelial cells: a comparative study of cell culture models

Pharm Res

Regulation of ciliary beat frequency by both PKA and PKG in bovine airway epithelial cells

Am J Physiol

Regulation of ciliary beat frequency by autonomic mechanisms: in vitro

J Appl Physiol

Stimulation of ciliary beat frequency by autonomic agonists: in vivo

J Appl Physiol

Effects of albuterol enantiomers on ciliary beat frequency in ovine tracheal epithelial cells

J Appl Physiol

Effect of cyclic AMP on ciliary function in rabbit tracheal epithelial cells

J Appl Physiol

Effect of cyclic AMP on ciliary activity of human respiratory epithelium

Eur Respir J

Lack of nitric oxide involvement in cholinergic modulation of ovine ciliary beat frequency

J Aerosol Med

Dual signal transduction mechanisms modulate ciliary beat frequency in upper airway epithelium

Am J Physiol

In vitro phosphorylation of Paramecium axonemes and permeabilized cells

Cell Motil Cytoskeleton

cAMP-stimulated phosphorylation of an axonemal polypeptide that copurifies with the 22S dynein arm regulates microtubule translocation velocity and swimming speed in Paramecium

Proc Natl Acad Sci U S A

Localization of PKA and PKG in bovine bronchial epithelial cells and axonemes

Am J Respir Crit Care Med

Cyclic AMP-dependent phosphorylation of a 26 kDa axonemal protein in ovine cilia isolated from small tissue pieces

Am J Respir Cell Mol Biol

Effects on Lung-cell Physiology
Effects of β-agonists on airway epithelial cells☆,☆☆

Lack of β₃-adrenergic receptor mRNA expression in adipose and other metabolic tissues in the adult human

Mechanism of action of β₂-adrenergic agonists

Control of the beat cycle of respiratory tract cilia by Ca²⁺ and cAMP