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Classical behavior of airway smooth muscle and the balance of static forces
- Bronchospasm and its biophysical basis in airway smooth muscle

The microstructure of striated muscle is highly ordered whereas there is abundant evidence in the literature demonstrating that the cytoskeletal matrix of smooth muscle is quite disordered [56,57]; it is, after all, its amorphous structure that gives 'smooth' muscle its name. Moreover, the cytoskeletal matrix of airway smooth muscle is in a continuous state of remodeling, a point to which we return below. Despite these differences, it has been widely presumed that to a first approximation Huxley's sliding filament model of muscle contraction [58] describes the function of both smooth and striated muscle [59-61]. For many of the biophysical phenomena observed in airway smooth muscle, such as active force generation and shortening velocity, Huxley's model represents a useful tool for thought [61], while for others, like mechanical plasticity, it does not.

As in the case of striated muscle contraction, the principal biophysical parameters that characterize the case of smooth muscle contraction include the maximum active isometric force (or stress, which is simply the force carried per unit area), the length at which the muscle can attain that maximal force (i.e., the optimum length, Lo), and the shortening capacity of the muscle. The sliding filament model of Huxley is the starting point for understanding each of these phenomena. As described by Huxley [58], isometric force, as well as muscle stiffness, are proportional to the number of acto-myosin cross links per unit volume. This is true because, assuming rigid filaments, all bridges within a given contractile unit must act mechanically in parallel, with their displacements being identical and their forces being additive. The maximum active stress supported by smooth vs. striated muscle is approximately the same and is of the order 105 Pascal. In striated muscle, the optimum length is attributed to the extent of overlap between the myosin filament and the actin filament, with optimum length corresponding to a maximum number of myosin heads finding themselves within striking distance of an available actin binding site, and the maximum capacity of the muscle to shorten being limited by the collision of the myosin filament end with the z-disc. Smooth muscle possesses no structure comparable to the z-disc, however, although actin filaments terminate in dense bodies, which might come into play in limiting muscle shortening. Whereas unloaded striated muscle can shorten perhaps 20% from its optimum length, unloaded smooth muscle can shorten as much as 70% [62-65]. Several physical factors may come into play to limit the capacity for unloaded shortening of smooth muscle. Small [56,57] has shown that the actin filaments of the contractile apparatus connect to the cytoskeleton at cytoplasmic dense bodies and with the longitudinal rib-like arrays of dense plaques of the membrane skeleton that couple to the extracellular matrix. Moreover, the side-polar configuration of the myosin filament [66,67] is likely to be involved. Still other factors coming into play include length-dependent activation [68,69], length-dependent rearrangements of the cytoskeleton and contractile machinery [27,70], and length-dependent internal loads [65,71,72].

What are the extramuscular factors that act to limit airway smooth muscle shortening? The basic notion, of course, is that muscle shortening stops when the total force generated by the muscle comes into a static balance with the load against which the muscle has shortened, both of which vary with muscle length. The factors setting the load include the elasticity of the airway wall, elastic tethering forces conferred by the surrounding lung parenchyma, active tethering forces conferred by contractile cells in the lung parenchyma [73,74], mechanical coupling of the airway to the parenchyma by the peribronchial adventitia, and buckling of the airway epithelium and submucosa [75-77]. In addition, the airway smooth muscle itself is a syncytium comprised mostly of smooth muscle cells, aligned roughly along the axis of muscle shortening, and held together by an intercellular connective tissue network. In order to conserve volume, as the muscle shortens it must also thicken. And as the muscle shortens and thickens, the intercellular connective tissue network must distort accordingly. Meiss has shown evidence to suggest that at the extremes of muscle shortening it may be the loads associated with radial expansion (relative to the axis of muscle shortening) of the intercellular connective tissue network that limits the ability of the muscle to shorten further [78].

In the healthy intact dog, airway smooth muscle possesses sufficient force generating capacity to close all airways [79,80]. This fact may at first seem to be unremarkable, but it is not easily reconciled with the observation that when healthy animals or humans are challenged with inhaled contractile agonists in concentrations thought to be sufficient to activate the muscle maximally, resulting airway narrowing is limited in extent, and that limit falls far short of airway closure [81,82]. Breathing remains unaccountably easy. Indeed, it is this lightness of breathing in the healthy challenged lung, rather than the labored breathing that is characteristic of the asthmatic lung, that in many ways presents the greater challenge to our understanding of the determinants of acute airway narrowing [83]. Brown and Mitzner [79] have suggested that the plateau of the dose-response curve reflects uneven or limited aerosol delivery to the airways. Another possibility, however, is that mechanisms exist that act to limit the extent of muscle shortening in the healthy breathing lung, whereas these mechanisms become compromised in the asthmatic lung. It has been suspected that the impairment of that salutary mechanism, if it could only be understood, might help to unlock some of the secrets surrounding excessive airway narrowing in asthma, as well as the morbidity and mortality associated with that disease [84-87]. This brings us to muscle dynamics, deep inspirations, and the potent effects of a time-varying muscle load associated with the act of breathing.

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