Frontiers reviewThe mechanics of exaggerated airway narrowing in asthma: the role of smooth muscle
Introduction
Non-specific airway or bronchial hyperresponsiveness (NSBH) is the exaggerated airway narrowing which occurs in response to airway challenge with a wide variety of pharmacological agonists and non specific irritants such as cold, dry air and oxidant gases. The stimuli which elicit the exaggerated response have in common the ability to directly or indirectly stimulate airway smooth muscle (ASM) to contract. NSBH is characterized both by an increase in the sensitivity of the airways (i.e. they narrow more easily than the airways of normal subjects at lower concentrations of pharmacologic agonists or lower levels of irritants than airways of normal subjects) and by greater maximal airway narrowing (i.e. the airways are capable of narrowing more than normal airways can be induced to narrow even at the highest dose of agonist) (Woolcock et al., 1984, Sterk et al., 1985). Despite the fact that NSBH is believed to be a basic mechanism underlying the labile airway narrowing which is characteristic of asthma, its mechanism remains unknown. Although increased sensitivity is important, making asthmatics prone to airway narrowing in response to otherwise trivial stimuli, it is the excessive maximal airway narrowing that represents the most important threat to their well being since it may result in incapacitating or life-threatening attacks of airway narrowing (Macklem, 1989, Sterk and Bel, 1989).
Although it is generally agreed that the narrowing is caused by contraction and shortening of the airway smooth muscle, it is still unclear if the phenomenon is due to fundamental changes in the phenotype (structure and/or behavior) of the smooth muscle itself or is caused by structural and/or mechanical changes in the non-contractile elements of the airway wall or by alterations in the relationship of the airway wall to the surrounding lung parenchyma.
The current paradigm for the pathophysiology of asthma involves the development of acute and chronic inflammation in the airways of genetically susceptible individuals. The acute airway inflammation causes airway narrowing by producing increased vascular permeability, edema, mucus hypersecretion and ASM contraction. Perpetuation of the inflammation, driven by TH2 lymphocytes, leads to structural and functional changes in the airways rendering them hyperresponsive. Symptomatic airway obstruction is due to both the episodes of acute inflammation and the chronic changes which, by causing NSBH, render asthmatics at risk of excessive narrowing when exposed to low levels of naturally occurring stimuli.
Although the allergic inflammation may be completely or partially reversible with allergen avoidance or anti-inflammatory therapy, the consequences of chronic inflammation reverse slowly and incompletely. NSBH increases during episodes of acute inflammation such as can be produced by allergen exposure (O’Byrne, 1988). Although the enhanced NSBH is transient, waning over a period of days or weeks, repeated naturally occurring episodes of allergic inflammation may lead to fixed NSBH (Cockcroft, 1985). This permanent derangement of airway function has been most clearly demonstrated in the long-term follow-up studies of patients who develop occupational asthma in response to exposure to substances such as toluidine diisocyanate (TDI) (Cockcroft, 1982) or plicatic acid (Western Red cedar asthma; (Chan-Yeung et al., 1984). If these individuals are removed from exposure early enough, there may be complete reversibility of airway hyperresponsiveness and a return to an asymptomatic status. When exposure is more prolonged, many individuals develop persistent NSBH and symptomatic asthma (Chan-Yeung et al., 1987).
Section snippets
Structural abnormalities in asthma
It is unclear what structural or functional changes in the airways are responsible for conferring persistent NSBH. In previous work we (James et al., 1989, Kuwano et al., 1993) and others (Ebina et al., 1990, Carroll et al., 1993) have examined the structural changes which occur in the airways of subjects who have chronic severe and moderate asthma and have attempted to predict, using animal models and computer simulations, the functional consequences of these structural changes (Wiggs et al.,
Functional alterations in ASM: in vitro studies
The computational model which was developed by Lambert et al. (1993) to explore the relative importance of remodeling of airway wall components suggested that the increase in the amount of ASM was the most important structural change contributing to NSBH in asthma. However the results of the modeling were based on a number of important assumptions which recent results suggest are no longer tenable. An important assumption was that the phenotype of the ASM was unchanged other than its increase
Functional alterations in ASM: in vivo studies
There is considerable evidence that changes in muscle stress and strain are important modulators of airway narrowing in vivo. It has been known for some time that a deep inspiration (DI) has a bronchodilating effect in normals especially after bronchoconstriction has been produced (Nadel and Tierney, 1966). Fish and coworkers were the first to report that the bronchodilating effect of a DI was less effective in asthmatics and atopics than in normals (Fish et al., 1977, Fish et al., 1978, Fish
Acknowledgements
Dr Greg King was supported by an Astra/MRC/PMAC Canada Fellowship. Dr Chun Seow is a MRC scholar. The work is supported by the MRC operating grants of Peter D Paré and Chun Seow.
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