Airway smooth muscle in asthma: flirting with disaster
Authors: JJ Fredberg
Journal: European Respiratory Journal (1998)

Airway hyperresponsiveness is the excessive narrowing of the airway lumen caused by stimuli that would cause little or no narrowing in the normal individual. It is one of the cardinal features of asthma but remains largely unexplained. Sometimes, though, clues to the greatest mysteries are right in front of us but we do not see them, and the role of breathing in airway hyperresponsiveness may be one of these clues. The smooth muscle surrounding the airway shortens when it is activated, and as the muscle shortens the airway narrows and breathing tends to become difficult. The lung has a potent built-in defence against bronchospasm, however, and this defence works in the opposite direction; the act of breathing makes it difficult for activated muscle to shorten [1–8]. Asthma is an inflammatory disease, but could it be that it is the failure of this particular defence mechanism which is the most telling end-effect of the inflammatory cascade, and therefore the proximal cause of airway hyperresponsiveness in asthma? This idea is not at all new [1], but the emergence of new evidence and new understanding of underlying mechanisms invites reconsideration of this question. We breathe all of the time and we sigh at the rate of about 10 times per hour [9]. The bronchodilating effect of this pattern of breathing is so effective that airway narrowing never approaches dangerous levels in healthy people, even when they fall into the hands of investigators who convince them to inhale high concentrations of bronchoconstricting agents. We can put the potency of this mechanism into perspective with the following observations. The expected physiological range of muscle stretch during spontaneous breathing is about 4–12% of muscle length whereas, in isolated activated muscle, tidal stretches of only 3% of muscle length are enough to inhibit active force generation by 50% [10]. By contrast, extremely high concentrations of isoproterenol (>10-6 M) are required to attain by purely pharmacological means the same degree of relaxation as is caused by the small tidal stretches which occur during breathing (unpublished observations). In healthy volunteers who inhale bronchoconstricting substances such as histamine, there is a reflex increase in the frequency and depth of spontaneous sighs when bronchospasm begins, and these deep inspirations cause prompt and nearly complete dilation of the airway [4, 11]. Even when healthy volunteers inhale some of the most potent known bronchoconstrictors, such as leukotrienes, appreciable bronchospasm cannot be demonstrated unless deep inspirations are prohibited [12]. Taking into account the endogenous levels at which various dilators are found in the airway, these observations suggest that the tidal muscle stretches which are attendant to spontaneous breathing comprise the first line of defence against bronchospasm, and that tidal muscle stretch may be the most potent of all known bronchodilating agents. In an asthmatic attack this bronchodilating mechanism fails. Indeed, there is ample evidence from the work of INGRAM and coworkers [11] to show that, if anything, in an asthmatic attack deep inspirations make matters worse. In this connection, experiments conducted years ago led FISH et al. [1] to the striking observation that airway obstruction in asthma behaves as if it were caused by an intrinsic impairment of the bronchodilating effect of a deep inspiration, as opposed to an inappropriate end-responsiveness of the airway itself. At about the same time, a similar observation led OREHEK et al. [4] to speculate that asthma triggers a vicious circle in which asthmatic airway obstruction increases the frequency of deep inspirations, and deep inspirations, in turn, make the obstruction worse. Although the underlying mechanism is unknown, the impairment of the bronchodilating effect of a deep inspiration is thought to be a feature characteristic of only the late-phase response to allergen challenge and of spontaneous asthmatic obstruction [11, 13]. Therefore, it came as a surprise to learn only recently that an impairment of this kind is easily evoked in completely healthy individuals. Two laboratories have shown that if healthy, nonasthmatic, nonallergic subjects do nothing more than to refrain voluntarily from taking deep inspirations, within 15 min their airways become hyperresponsive to a degree that is virtually indistinguishable from that observed in asthmatic subjects [3, 14, 15]. Even more remarkably, when deep inspirations are eventually reinstated, the subsequent ability of deep inspirations to dilate the airways becomes profoundly impaired, just as it does in spontaneous asthmatic obstruction. Put simply, it is as if the airway smooth muscle, when activated, is all the time flirting with disaster and the mere removal of deep inspirations, which would seem superficially to be a rather trivial matter, is sufficient nonetheless to allow this flirtation to progress to a situation that is much more serious, even in healthy volunteers with no airway inflammation, no history of airway inflammation or allergy, and possessing airways and airway smooth muscle that are perfectly normal. How is all this to be explained? Many mechanisms have been invoked, but perhaps the simplest may lie at the level of the cyclic interaction of myosin with actin, the molecular motor within the airway smooth muscle. When muscle contracts it also becomes stiff [10]. The muscle stiffens when activated because the binding of myosin to actin, Correspondence: J.J. Fredberg, Dept of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA. Fax: 1 6174323468.