Mechanotransduction, asthma, and airway smooth muscle - PubMed (original) (raw)

Mechanotransduction, asthma, and airway smooth muscle

Ben Fabry et al. Drug Discov Today Dis Models. 2007.

Abstract

Excessive force generation by airway smooth muscle is the main culprit in excessive airway narrowing during an asthma attack. The maximum force the airway smooth muscle can generate is exquisitely sensitive to muscle length fluctuations during breathing, and is governed by complex mechanotransduction events that can best be studied by a hybrid approach in which the airway wall is modeled in silico so as to set a dynamic muscle load comparable to that experienced in vivo.

PubMed Disclaimer

Figures

Fig. 1

Fig. 1

Schematic cross-section of an airway and surrounding lung parenchyma. The airway is held open by the tethering stress of the lung parenchyma (Pp) and is constricted by the airway smooth muscle tension (τmuscle). Other forces that can either open or close the airway result from the differences between the alveolar pressure (Palv) and airway lumen pressure (Plumen), and the passive tension from stretching or compressing the airway wall tissue (τwall).

Fig. 2

Fig. 2

Steady-state load curve according to Eq. 1 for an 8th generation human airway during quiet breathing and deep inspiration. Here, the lumen and alveolar pressure are assumed to be equilibrated (zero flow condition), hence transpulmonary pressure equals pleura pressure. The load curve is normalized to the maximal force F0 that the smooth muscle of that airway can generate, and to a reference radius rref of the unconstricted airway at a transmural pressure of 10 cmH2O.

Fig. 3

Fig. 3

Smooth muscle response to large-scale force and length perturbations shows non-reversible behavior attributable to cytoskeletal remodeling. A: Muscle length vs. time during stimulation with acetylcholine. The first 120 min correspond to an isotonic shortening at F = 0.32 F0. The muscle lengthens in response to sinusoidal force perturbations with amplitudes between 4% and 32% of maximum force (F0) around a mean force of 0.32 F0. After force perturbations are reduced to 8%, the muscle shortens incompletely (arrow). Adapted from Ref. [5]. B: Force vs. time during an isometric contraction at length L = L0. After 10 min, the muscle length is reduced to 0.7 L0. The subsequent force recovery is incomplete (arrow). Adapted from Ref. [12].

Fig. 4

Fig. 4

Length of fully activated smooth muscle in an 8th generation human airway for a static load (constant pleural pressure of 4 cmH2O) and a dynamic load. The dynamic load consisted of quiet breathing (pleural pressure amplitude 1.25 cmH2O, 12 breaths/min), punctuated by deep inspirations (10 cmH2O amplitude every 6 min). Muscle length was measured under the loading conditions for a normal airway, a mildly asthmatic airway with a 2-fold increase in smooth muscle mass, and a severely asthmatic airway with a 5-fold increase in smooth muscle mass. Dynamic loading lead to a substantial bronchodilation for both the normal and the mildly asthmatic airway, but failed to relax the severely asthmatic airway. Adapted from Ref. [38].

Similar articles

Cited by

References

    1. Gunst SJ, et al. Mechanisms for the mechanical plasticity of tracheal smooth muscle. Am J Physiol. 1995;268(5 Pt 1):C1267–1276. - PubMed
    1. Fredberg JJ, et al. Friction in airway smooth muscle: mechanism, latch, and implications in asthma. J Appl Physiol. 1996;81(6):2703–2712. - PubMed
    1. Fredberg JJ, et al. Airway smooth muscle, tidal stretches, and dynamically determined contractile states. Am J Respir Crit Care Med. 1997;156(6):1752–1759. - PubMed
    1. Raboudi SH, et al. Dynamically determined contractile states of airway smooth muscle. Am J Respir Crit Care Med. 1998;158(5 Pt 3):S176–178. - PubMed
    1. Fredberg JJ, et al. Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in bronchospasm. Am J Respir Crit Care Med. 1999;159(3):959–967. - PubMed

Grants and funding

LinkOut - more resources