Airway smooth muscle in asthma. Perturbed equilibria of myosin binding.

Abstract

The classic theory of airway lumen narrowing was developed to explain the determinants of airway narrowing, and why that narrowing can become excessive in asthma. The classic theory emphasizes that muscle length and airway caliber are set by a force balance in which the active force generated by airway smooth muscle statically is in mechanical equilibrium with the passive reaction force developed by the elastic load against which that muscle has shortened. Since both forces depend on muscle length, the muscle accommodates itself to the length at which these opposing forces come into static balance (1, 2). If the external load should change in time, as would occur with lung inflation, for example, then the activated muscle is believed to accommodate itself to a sequence of states lying along its static force–length characteristic (3–6). The isometric forcegenerating capacity of airway smooth muscle is set principally by muscle mass, muscle contractility, and muscle position on its static force–length characteristic (2, 7). Taken together, evidence available in the literature suggests that there is no systematic difference in force-generating capacity between muscle from the normal versus the asthmatic lung, although this evidence is equivocal (8, 9). Moreover, animal studies now suggest that the force-generating capacity of normal airway smooth muscle is, in any event, more than sufficient to close all airways in the lung (10, 11). The passive reaction force against which the muscle shortens is set principally by the elasticity and geometry of the airway wall, tethering of the airway to the lung parenchyma, and the state of lung inflation (5, 11, 12). Each of these factors, in turn, has its own determinants that are known to be modified with chronic airway inflammation (13, 14). This classic framework explained much of what needed to be explained, but our understanding of the causality linking airway inflammation to its ultimate mechanical consequence— excessive airway narrowing—remains fragmentary. For example, for reasons that remain poorly understood the plateau of the dose–response curve is elevated in asthma, or abolished altogether, suggesting that those factors that limit maximal airway narrowing in the normal lung, whatever they are, have somehow been attenuated in the asthmatic lung. And no less important than the mystery of the plateau is the perplexing role of deep inspirations (3, 15–18). Deep inspirations that are attendant to spontaneous breathing may be the most potent of all known bronchodilating agencies, and they comprise the first line of defense against bronchospasm. But in the spontaneous asthmatic attack this potent bronchodilating mechanism fails. Indeed, Fish and colleagues (16) suggested that it may be the failure of this very defense mechanism that is the most telling end effect of the inflammatory cascade and, therefore, the proximal cause of excessive airway narrowing in asthma. Moreover, there is ample evidence from the work of Ingram and colleagues (17–19) to show that, if anything, in an asthmatic attack deep inspirations only make matters worse. The inability of deep inspirations to relax airway smooth muscle during episodes of spontaneous asthmatic obstruction remains unexplained.