What Evidence Implicates Airway Smooth Muscle in the Cause of BHR?

Abstract

Bronchial hyperresponsiveness (BHR), the occurrence of excessive bronchoconstriction in response to relatively small constrictor stimuli, is a cardinal feature of asthma. Here, we consider the role that airway smooth muscle might play in the generation of BHR. The weight of evidence suggests that smooth muscle isolated from asthmatic tissues exhibits normal sensitivity to constrictor agonists when studied during isometric contraction, but the increased muscle mass within asthmatic airways might generate more total force than the lesser amount of muscle found in normal bronchi. Another salient difference between asthmatic and normal individuals lies in the effect of deep inhalation (DI) on bronchoconstriction. DI often substantially reverses induced bronchoconstriction in normals, while it often has much less effect on spontaneous or induced bronchoconstriction in asthmatics. It has been proposed that abnormal dynamic aspects of airway smooth muscle contraction velocity of contraction or plasticity- elasticity balance might underlie the abnormal DI response in asthma. We suggest a speculative model in which abnormally long actin filaments might account for abnormally increased elasticity of contracted airway smooth muscle.

Latrunculin B increases force fluctuation-induced relengthening of ACh-contracted, isotonically shortened canine tracheal smooth muscle

“…To test this hypothesis, we assessed the effects of latrunculin B (which sequesters G-actin, thus preventing filament polymerization and lengthening) and jasplakinolide (which stabilizes actin filaments by blocking their degradation), on isometric, auxotonic, and isotonic contraction of canine tracheal smooth muscle (TSM). We reasoned that sequestration of actin monomers with latrunculin B should decrease contractile filament length and so should result in increased force fluctuation-induced relengthening, as our lab-oratory has proposed previously (2,28). Furthermore, stabilization of polymerized actin with jasplakinolide should block the latrunculin effect.…”

“…Previously, we hypothesized that the length of contractile actin filaments should play an important role in determining the plastic behavior of contracted airway muscle (2,28). Our rationale was that, on stress-induced periodic lengthening of muscle (as during deep breathing) with short actin filaments, myosin filaments might have to undergo parallel to series rearrangement in order for cross-bridge formation and force generation to continue.…”

“…Based on these observations, we hypothesized that actin filament length plays an important role in determining force fluctuation-induced relengthening of contracted airway muscle (2,28). To test this hypothesis, we assessed the effects of latrunculin B (which sequesters G-actin, thus preventing filament polymerization and lengthening) and jasplakinolide (which stabilizes actin filaments by blocking their degradation), on isometric, auxotonic, and isotonic contraction of canine tracheal smooth muscle (TSM).…”

Force Fluctuation induced Relengthening of Acetylcholine-contracted Airway Smooth Muscle

“…We reasoned that if individuals with asthma had longer actin filaments in their airway smooth muscle, the contractile units would not need to adapt as readily to stretch elicited by tidal breathing or deep inspiration (26)(27)(28). Without the need for rearrangement of contractile units, the airway smooth muscle of an individual with asthma could re-contract immediately after the stretch imposed on the bronchi by the lung-tethering forces.…”

“…Longer actin filaments in people with asthma are not that hard to hypothesize, since the environment in asthmatic, inflamed airways is rife with cytokines and mediators that promote hypertrophy and hyperplasia in most of the tissues in the bronchiolar wall (28,29). Furthermore, it is well established that stress, stretch, and cytokines can directly activate p38 MAPK, an upstream regulator of HSP27 and actin filament length (23,24,31).…”