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Biology Articles » Biophysics » Bronchospasm and its biophysical basis in airway smooth muscle » Airway hyperresponsiveness

Airway hyperresponsiveness
- Bronchospasm and its biophysical basis in airway smooth muscle

It was recognized quite early that the lung is an irritable organ and that stimulation of its contractile machinery in an animal with an open chest can cause an increase in lung recoil, air to be expelled, a rise in intratracheal pressure, and an increase in airways resistance [28-31]. However, until the second half of the last century airway smooth muscle was not regarded as being a tissue of any particular significance in respiration mechanics [28]. A notable exception in that regard was Salter [32], who, in 1859, was well aware of the existence of airway smooth muscle and its potential role in asthma. Airway smooth muscle was first described in 1804 by Reisseisen (as related by Otis [28]) and its functional properties first considered by Einthoven [33] and Dixon and Brodie [31]. More recent studies have shown that the fraction of the tissue volume that is attributable to contractile machinery is comparable for airways, alveolated ducts and blood vessels in the lung parenchyma [34]; the lung parenchyma, like the airway, is a contractile tissue [35-39]. Airway smooth muscle is now recognized as being the major end-effector of acute airway narrowing in asthma [18,21]. There is widespread agreement that shortening of airway smooth muscle is the proximal cause of excessive airway narrowing during an asthmatic attack [17], with swelling of airway wall compartments and plugging by airway liquid or mucous being important amplifying factors [18,40]. It remains unclear, however, why in asthma the muscle can shorten excessively.

Airway hyperresponsiveness is the term used to describe airways that narrow too easily and too much in response to challenge with nonspecific contractile agonists [41]. Typically, a graph of airways resistance vs. dose is sigmoid in shape (Fig. 1); the response shows a plateau at high levels of contractile stimulus. Generally, the existence of the plateau is interpreted to mean that the airway smooth muscle is activated maximally and, therefore, has shortened as much as it can against a given elastic load. Once on the plateau, therefore, any further increase in stimulus can produce no additional active force, muscle shortening, or airway resistance.

To say that airways narrow too easily, then, means that the graph of airways resistance vs. dose of a non-specific contractile stimulus is shifted to the left along the dose axis, and that airways respond appreciably to levels of stimulus at which the healthy individual would be unresponsive; this phenomenon is called hypersensitivity. By contrast, to say that the airways narrow too much means that the level of the plateau response is elevated, or that the plateau is abolished altogether, regardless of the position of the curve along the dose-axis; this phenomenon is called hyperreactivity. As distinct from hypersensitivity, it is this ability of the airways to narrow excessively, with an elevated or abolished plateau, that accounts for the morbidity and mortality associated with asthma [42].

It has long been thought that the factors that cause hypersensitivity vs. hyperreactivity are distinct, with the former being associated with receptor complement and downstream signaling events but the latter being associated with purely mechanical factors, including the contractile apparatus, the cytoskeleton, and the mechanical load against which the muscle shortens [16,18,21,43]. Macklem has pointed out that once the muscle has become maximally activated it is the active force and the load that become all important, and the plateau response becomes essentially uncoupled from underlying biochemistry, signaling and cell biology [20-22]. As described below, there is reason to think that these distinctions may not be as clear as once believed, however.

Although asthma is usually defined as being an inflammatory disease, the link between the immunological phenotype and the resulting mechanical phenotype associated with disease presentation, including airways hyperresponsiveness, remains unclear; indeed, it is now established that airway hyperresponsiveness can be uncoupled from airway inflammation [44-47]. It remains equally unclear if airway hyperresponsiveness is due to fundamental changes within the smooth muscle itself, as might be caused by inflammatory mediators, chemokines and cytokines [48], or due to changes external to the muscle such as a reduced mechanical load against which the smooth muscle contracts. Still another possibility supported by recent evidence is that there is an interaction of the two wherein the contractile machinery within the smooth muscle cell adapts in response to a change in its mechanical microenvironment [1,17,24,25,27,49,50]. Moreover, Tschumperlin and colleagues [51,52] have provided evidence to suggest that bronchospasm can lead to mechanically-transduced pro-inflammatory signaling events in the airway epithelium, in which case inflammation may cause bronchospasm, but bronchospasm in turn may amplify or even cause inflammation.

In the balance of this review I address the classical picture of smooth muscle behavior and then go on to describe what we know about non-classical behavior in a dynamic mechanical environment driven by the tidal action of breathing. In addition, in recent years we have come to learn that the mechanical environment leads to interesting airway instabilities and adaptation in the muscle itself. Finally, I conclude by providing an emerging integrative context that seems to account for many of these properties that are not accounted for in classical perspectives of smooth muscle biophysics. I do not address the increasing evidence that now suggests that cytokines such as IL-1β and TNFα augment responses to bronchoconstrictor agonists while attenuating the bronchodilation that can be effected by hormones and paracrine agents like epinephrine and PGE2 [53]. Such cytokines, along with growth factors and other inflammatory mediators also result in smooth muscle hyperplasia, at least in culture systems [5]. In culture, extracellular matrix proteins also influence the contractile phenotype of airway smooth muscle cells [54,55]. Whether asthmatic inflammation can result in a hypercontractile phenotype remains to be established.


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