Nonbronchodilator Pulmonary Effects
Effect of β-adrenergic agonists on mucociliary clearance☆,☆☆

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Abstract

The mucociliary clearance apparatus, an important defense mechanism for clearing the lung of bacteria and foreign particulate matter, is a well-coordinated system consisting of airway secretory cells that produce a sol and gel (or mucus) fluid layer on the airway surface and ciliated cells that propel the mucus out of the lung towards the mouth. In vivo mucociliary clearance rates can be measured by following the rate of egress of deposited, radiolabeled markers by gamma camera. Short-acting β-adrenergic agonists have been shown to enhance mucociliary clearance rates to varying degrees in patients with various lung diseases (eg, asthma, chronic bronchitis, and cystic fibrosis), although the enhancement is generally less than that seen in the normal lung. Limited data on the in vivo dose-response relationships of these mucociliary clearance effects suggest that larger doses are required for enhancement of mucociliary clearance than are needed for bronchodilatation. Little is known about chronic effects, but studies with dosing for up to a week also suggest an enhancement of mucociliary clearance, primarily by agonists that are lipophilic. Issues for future research include the effects of the newer long-acting β-agonists, large versus small airway effects, and combination effects with other inhaled therapeutic agents (eg, steroids and ion-channel blockers). (J Allergy Clin Immunol 2002;110:S291-7.)

Section snippets

Effect of β-agnoists on components of mucociliary clearence apparatus

The in vitro enhancement of ciliary beat frequency by β-adrenergic agonists has been clearly demonstrated for nearly all such agents tested.1, 2, 3, 4 This increase is mediated through β-adrenergic receptors, as evidenced by the ability to block the response with the selective β-adrenergic blocker propranolol.3 Wong et al5 tested a β-agonist, aerosolized fenoterol (10−5 mol/L), in an in vivo canine preparation and confirmed that the ciliostimulatory effect could be observed in the intact

Measurement of in vivo mucociliary clearence rates

Mucociliary clearance rates can be measured in human beings by assuming that a nonpermeating, inhaled marker depositing on the airway surface moves out of the lung at the same rate as the airway secretions in which it is immersed. The most common technique is to use inhaled radiolabeled particles, aqueous or dry, that on deposition in the lung can be followed by gamma camera or scintillation detectors to determine their rate of egress from the lung. Technetium 99m, generally the isotope of

Acute effect of β-agnoists on mucociliary clearence in health and disease

There have been numerous studies with a variety of β-agonists and routes of administration showing acute, single-dose enhancement of whole-lung clearance and TMV in healthy human subjects.1, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 However, β-agonists appear to be less capable of stimulating clearance in patients with the various airway diseases discussed previously than in healthy subjects. A comparison of studies within a given laboratory for various types of patients illustrates these

Dose required for enhanced mucociliary clearence versus bronchodilatation

The relative dose required of a β-agonist to acutely stimulate mucociliary clearance is likely greater than that required to produce bronchodilatation. In a pilot study preceding our study on the effect of β-adrenergic stimulation on retention of particles 24 to 48 hours after deposition,32 we found that we could produce significant bronchodilatation in healthy subjects with 3 minutes of nebulized albuterol inhalation with no acute enhancement of whole-lung mucociliary clearance (Fig 2).

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Subchronic β-adrenergic effects on mucociliary clearence

There have been no long-term studies (dosing for >1 week) on the chronic effects of inhaled β-agonists on mucociliary clearance in human beings. Some, however, have investigated the effects of repeated dosing with various agonists for as long as 1 week and found either no effect on mucociliary clearance31, 41, 42 or a significant enhancement.43, 44 One of the difficulties in performing these studies is to ensure that the inhaled radioaerosol deposition pattern on study days after subchronic

Future directions

As described previously, it is clear that β-agonists administered orally, subcutaneously, or by inhalation acutely stimulate mucociliary clearance. What is less clear is how long-term use of these agonists may chronically affect the mucociliary clearance apparatus in either a beneficial or detrimental manner. Although chronic dosing studies are more difficult and time-consuming, more of them should be performed. In addition, there has been little study of the newer long-acting agonists (eg,

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    ☆

    Supported by US Environmental Protection Agency Cooperative Agreement 824915 and CF Foundation grant DONALD00A0.

    ☆☆

    Reprint requests: William D. Bennett, PhD, Center for Environmental Medicine, CB 7310, 104 Mason Farm Rd, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.

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