Airway Smooth Muscle, Tidal Stretches, and Dynamically Determined Contractile States

Abstract

In the classic theory of airway lumen narrowing in asthma, active force in airway smooth muscle is presumed to be in static mechanical equilibrium with the external load against which the muscle has shortened. This theory is useful because it identifies the static equilibrium length toward which activated airway smooth muscle would tend if given enough time. The corresponding state toward which myosin-actin interactions would tend is called the latch state. But are the concepts of a static mechanical equilibrium and the latch state applicable in the setting of tidal loading, as occurs during breathing? To address this question, we have studied isolated, maximally contracted bovine tracheal smooth muscle subjected to tidal stretches imposed at 0.33 Hz. We measured the active force (F) and stiffness (E), which reflect numbers of actin-myosin interactions, and hysteresivity (eta) which reflects the rate of turnover of those interactions. When the amplitude of imposed tidal stretch (epsilon) was very small, 0.25% of muscle optimal length, the steady-state value of F approximated the isometric force, E was large, and eta was small. When epsilon was increased beyond 1%, however, F and E promptly decreased and eta promptly increased. The muscle could be maintained in these steady, dynamically determined contractile states for as long as the tidal stretches were sustained; when epsilon subsequently decreased back to 0.25%, F, E, and eta returned slowly toward their previous values. The provocative stretch amplitude required to cause active force or muscle stiffness to fall by half, or hysteresivity to double, was slightly greater than 2%. These observations are consistent with a direct effect of stretch upon bridge dynamics in which, with increasing tidal stretch amplitude, the number of actin-myosin interactions decreases and their rate of turnover increases. We conclude that the interactions of myosin with actin are at every instant tending toward those that would prevail in the isometric steady state, but tidal changes of muscle length cause an excess in the rate of detachment. These stretch-induced detachment events can come so fast compared with the rate of attachment that static equilibrium conditions are never attained. If so, then airway lumenal narrowing and the underlying contractile state would be governed by a dynamic mechanical process rather than by a mechanical equilibrium of static forces.

Deep breaths, methacholine, and airway narrowing in healthy and mild asthmatic subjects

“…The finding of study 1 that the deep breaths blunted the decrease of FEV 1 and FVC but not of measurements not preceded by a full inflation, such as V part, RVpart, FRC, and sGaw, suggests a mechanism facilitating the distensibility of contracted airways rather than inhibiting airway smooth muscle shortening. In healthy subjects, the disappearance of the effect of prior deep breaths on the decrease of FEV 1 and FVC after 10 min of prohibition of further deep breaths may reflect a progressive increase in airway smooth muscle stiffness when the contractile apparatus is no more urged to change configuration with large lung inflations (3,5). This is consistent with in vitro data showing that the tone of airway smooth muscle is fully recovered under static conditions within 8 min after a large stretch (4).…”

“…The difference in the effect of the deep breaths on FEV 1 and FVC between healthy and asthmatic subjects, but not on the parameters not preceded by a full inflation, may be interpreted as reflecting greater airway stiffness in asthma (7,8). According to the latch-bridge theory (15), unstretched airway smooth muscle goes into a "frozen" state characterized by less hysteresivity and greater stiffness (3). Therefore, a reduced ability of the full inflations to distend constricted airways would reflect a greater proportion of latch bridges formed in asthma during prohibition of the deep inspirations preceding MCh inhalation.…”

Mechanotransduction, asthma and airway smooth muscle

“…Accordingly, a brief, transient force increase leads to a long-lasting lengthening of the muscle, and a brief, transient length increase leads to a long-lasting force reduction and softening of the muscle. These model predictions have been qualitatively confirmed in numerous smooth muscle studies [2][3][4][5]8].…”

“…Such a force balance need not be static in the sense that the degree of airway constriction reaches a steadystate, and indeed, over the past decade numerous experimental and theoretical studies have shown that airway caliber is equilibrated dynamically rather than statically [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. Indeed, the force-length curve of activated smooth muscle is constantly changing as the muscle adapts to its mechanical surroundings, such as the length to which it is stretched or the load against which it must contract.…”

Airway Bistability Is Modulated by Smooth Muscle Dynamics and Length-Tension Characteristics

“…Certainly ASM is known to exhibit different behavior when forced at higher frequencies (29), and airway-ASM coupling on shorter timescales is certainly an area worth investigating more carefully; for example, FIGURE 5 Changes in pressure-radius hysteresis curves, using the implied tension transfer function, as ASM activation is varied for fixed order (left) and as airway order is varied for fixed activation (right). Color coding as in Fig.…”