Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma.As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling.Anti-inflammatory therapy, however, does not ''cure'' asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM.In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

The large volume changes of some hollow viscera require a greater length range for the smooth muscle of their walls than can be accommodated by a fixed array of sliding filaments. A possible explanation is that smooth muscles adapt to length changes by forming variable numbers of contractile units in series. To test for such plasticity we examined the muscle length dependence of shortening velocity and compliance, both of which will vary directly with the number of thick filaments in series. Dog tracheal smooth muscle was studied because its cells are arrayed in long, straight, parallel bundles that span the length of the preparation. In experiments where muscle length was changed, both compliance and velocity showed a strong dependence on muscle length, varying by 1.7-fold and 2.2-fold, respectively, over a threefold range of length. The variation in isometric force was substantially less, ranging from a 1.2-to 1.3-fold in two series of experiments where length was varied by twofold to an insignificant 4% variation in a third series where a threefold length range was studied. Tetanic force was below its steady level after both stretches and releases, and increased to a steady level with 5-6 tetani at 5 rain intervals. These results suggest strongly that the number of contractile units in series varies directly with the adapated muscle length. Temporary force depression after a length change would occur if the change transiently moved the filaments from their optimum overlap. The relative length independence of the adapted force is explained by the reforming of the filament lattice to produce optimum force development, with commensurate changes of velocity and compliance.

It has been shown that deep inspiration (DI) taken before application of bronchoconstricting stimuli causes a reduction in the subsequent bronchoconstriction; a fast DI has a greater inhibitory effect than a slow DI. We hypothesize that periodic length changes imposed on a relaxed airway smooth muscle (ASM) would attenuate subsequent bronchoconstriction by disrupting the organization of the contractile apparatus, and this could be an important mechanism for the observed bronchoprotective effect of DI and tidal breathing. Length oscillations of different amplitude, frequency, and duration were applied to a relaxed muscle. The effects of such perturbations on force development were then assessed. Results show that oscillations reduce the subsequent force generation and that the magnitude of force reduction is proportional to amplitude and duration of the length oscillation. After the oscillation, isometric force recovered to the preoscillation level in a series of isometric contractions, and the rate of recovery was facilitated by frequent stimulation. The in vitro behavior of ASM found in this study could account for the observed temporary reduction in bronchoconstriction subsequent to a DI.

The ability of rabbit trachealis to undergo plastic adaptation to chronic shortening or lengthening was assessed by setting the muscle preparations at three lengths for 24 h in relaxed state: a reference length in which applied force was approximately 1-2% of maximal active force (P(o)) and lengths considerably shorter and longer than the reference. Passive and active length-tension (L-T) curves for the preparations were then obtained by electrical field stimulation at progressively increasing muscle length. Classically shaped L-T curves were obtained with a distinct optimal length (L(o)) at which P(o) developed; however, both the active and passive L-T curves were shifted, whereas P(o) remained unchanged. L(o) was 72% and 148% that of the reference preparations for the passively shortened and lengthened muscles, respectively. The results suggest that chronic narrowing of the airways could induce a shift in the L-T relationship of smooth muscle, resulting in a maintained potential for maximal force production.

Airway smooth muscle adapts to different lengths with functional changes that suggest plastic alterations in the filament lattice. To look for structural changes that might be associated with this plasticity, we studied the relationship between isometric force generation and myosin thick filament density in cell cross sections, measured by electron microscope, after length oscillations applied to the relaxed porcine trachealis muscle. Muscles were stimulated regularly for 12 s every 5 min. Between two stimulations, the muscles were submitted to repeated passive +/- 30% length changes. This caused tetanic force and thick-filament density to fall by 21 and 27%, respectively. However, in subsequent tetani, both force and filament density recovered to preoscillation levels. These findings indicate that thick filaments in airway smooth muscle are labile, depolymerization of the myosin filaments can be induced by mechanical strain, and repolymerization of the thick filaments underlies force recovery after the oscillation. This thick-filament lability would greatly facilitate plastic changes of lattice length and explain why airway smooth muscle is able to function over a large length range.

Smooth muscle cells line the walls of hollow organs and control the organ dimension and mechanical function by generating force and changing length. Although significant progress has been made in our understanding of the molecular mechanism of actomyosin interaction that produces sliding of actin (thin) and myosin (thick) filaments in smooth muscle, the sarcomeric structure akin to that in striated muscle, which allows the sliding of contractile filaments to be translated into cell shortening has yet to be elucidated. Here we show evidence from porcine airway smooth muscle that supports a model of malleable sarcomeric structure composed of contractile units assembled in series and in parallel. The geometric organization of the basic building blocks (contractile units) within the assembly and the dimension of individual contractile units can be altered when the muscle cells adapt to different lengths. These structural alterations can account for the different length-force relationships of the muscle obtained at different adapted cell lengths. The structural malleability necessary for length adaptation precludes formation of a permanent filament lattice and explains the lack of aligned filament arrays in registers, which also explains why smooth muscle is `smooth'.

Airway smooth muscle is able to adapt and maintain a nearly constant maximal force generation over a large length range. This implies that a fixed filament lattice such as that found in striated muscle may not exist in this tissue and that plastic remodeling of its contractile and cytoskeletal filaments may be involved in the process of length adaptation that optimizes contractile filament overlap. Here, we show that isometric force produced by airway smooth muscle is independent of muscle length over a twofold length change; cell cross-sectional area was inversely proportional to cell length, implying that the cell volume was conserved at different lengths; shortening velocity and myosin filament density varied similarly to length change: increased by 69.4% Ϯ 5.7 (SE) and 76.0% Ϯ 9.8, respectively, for a 100% increase in cell length. Muscle power output, ATPase rate, and myosin filament density also have the same dependence on muscle cell length: increased by 35.4% Ϯ 6.7, 34.6% Ϯ 3.4, and 35.6% Ϯ 10.6, respectively, for a 50% increase in cell length. The data can be explained by a model in which additional contractile units containing myosin filaments are formed and placed in series with existing contractile units when the muscle is adapted at a longer length. muscle contraction; myosin filaments; ATPase activity; electron microscopy RECENT STUDIES HAVE DEMONSTRATED that the cycle of contraction and relaxation in airway smooth muscle involves polymerization and depolymerization of the actin (9, 13) and myosin (6) filaments. This lability of contractile filaments during muscle activation resembles that of nonmuscle motile cells that rely on impromptu assembly of contractile apparatus for motility. Oscillatory strains applied to single airway smooth muscle cells have revealed plastic deformation similar to that observed in soft glassy materials (3). Functional studies of airway smooth muscle indicate that the cells maintain maximal isometric force production (optimal contractile filament overlap) over a threefold length change by varying the number of contractile units in series (15). This newly emerged "plasticity" model of smooth muscle contraction is incompatible with the current concept of contraction based on the relatively restrictive model of striated muscle that possesses filament arrays in fixed lattice, which cannot accommodate large changes in cell length without compromising force production (4).The feasibility of the plasticity model can be tested experimentally based on the model predictions: the recruitment of additional contractile units in muscles adapted to longer lengths should result in an increase in thick filament content (or mass) in individual muscle cells, and as a consequence, the metabolic rate should increase with muscle length. In the present study, we tested the plasticity hypothesis through quantitative analysis of mechanical properties and ultrastructure, and measurement of the rate of ATP consumption in airway smooth muscles adapted to different lengths. MATERIALS AND METHODSMuscl...

Vascular smooth muscle shows both plasticity and heterogeneity with respect to Ca2+ signaling. Physiological perturbations in cytoplasmic Ca2+ concentration ([Ca2+]i) may take the form of a uniform maintained rise, a transient uniform [Ca2+]i elevation, a transient localized rise in [Ca2+]i (also known as spark and puff), a transient propagated wave of localized [Ca2+]i elevation (Ca2+ wave), recurring asynchronous Ca2+ waves, or recurring synchronized Ca2+ waves dependent on the type of blood vessel and the nature of stimulation. In this overview, evidence is presented which demonstrates that interactions of ion transporters located in the membranes of the cell, sarcoplasmic reticulum, and mitochondria form the basis of this plasticity of Ca2+signaling. We focus in particular on how the junctional complexes of plasmalemma and superficial sarcoplasmic reticulum, through the generation of local cytoplasmic Ca2+ gradients, maintain [Ca2+]i oscillations, couple these to either contraction or relaxation, and promote Ca2+ cycling during homeostasis.