Small Airways and Asthma
An Important Therapeutic Target?

PETER H. HOWARTH

University of Southampton School of Medicine, Southampton, United Kingdom

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This supplement critically assesses the state of knowledge about the site of airway disease in asthma, reviewing the physiologic, pathologic, and clinical knowledge concerning the relative involvement of large and small airways in the disease's pathogenesis. This review is prompted by the increasing histopathologic evidence of inflammation within the small airways in asthma, as well as the presence of chronic structural airway changes at this site (1). How important are these small airway processes to symptom expression and abnormal physiology? Do the currently available anti-inflammatory therapies target these airways, and is such targeting important for the optimal clinical response? These issues were raised at a 1997 workshop sponsored by 3M Pharmaceuticals at the American Thoracic Society meeting in San Francisco, at which the current state of knowledge about the embryologic development of small airways and their involvement in the asthmatic process was presented. This supplement reflects this knowledge, highlighting areas of information and ignorance. It is apparent that the small airways have largely been underevaluated in asthma due to the difficulty of in vivo sampling and lack of specificity of physiologic measurements for this site. Analysis of postmortem tissue and resected lung tissue does, however, demonstrate that extensive disease exists in these airways. Further studies with drug delivery systems targeted at small airways, as well as large ones, will help to address their relevance to the clinical expression of asthma.

Inefficient drug delivery systems for inhalation therapy have been accepted pragmatically in the management of asthma, as long as they deliver a sufficient dose to achieve a clinical response (4). In this respect, the greatest use has been made of metered-dose inhalers, which use chlorinated fluorocarbons (CFCs) as propellants. The realization that CFCs were damaging the earth's ozone layer and therefore potentially harming world health led, in 1987, to the Montréal Protocol for discontinuing the use and manufacture of CFCs. There was a medical exemption until alternative drug delivery systems could be developed. This has led to improved technology, particularly dry powder delivery devices that do not require propellants and a new class of metered-dose inhaler that uses a hydrofluoralkane (HFA) as a propellant.

With the development of new inhalant devices for asthma therapy, it is pertinent to reconsider what the therapeutic target is, whether that target is optimal, and how treatment is best achieved. Although a few studies have attempted to address these issues for bronchodilators (8), for which lung function measurements provide a rapid indicator of response, they have largely been ignored for inhaled anti-inflammatory therapy due to the difficulties in determining the optimal measure of response. Furthermore, until recently the available imaging methods have lacked the specificity to clearly define the site of drug deposition within the airways. The standard approach involves planar imaging (13, 14). This technique views the lungs in two dimensions; although it divides the lung into central and peripheral sites, the central region will inevitably include overlying peripheral lung tissue. Planar imaging thus lacks the specificity to discern spatial distribution, and this limitation helps account for the variable findings to date (8- 12). It is only with the recent development of single photon emission computed tomography that an accurate in vivo assessment of deposition sites has become available, allowing these issues to be addressed (15).

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