A biomechanical model of agonist-initiated contraction in the asthmatic airway.

This paper presents a modelling framework in which the local stress environment of airway smooth muscle (ASM) cells may be predicted and cellular responses to local stress may be investigated. We consider an elastic axisymmetric model of a layer of connective tissue and circumferential ASM fibres embedded in parenchymal tissue and model the active contractile force generated by ASM via a stress acting along the fibres. A constitutive law is proposed that accounts for active and passive material properties as well as the proportion of muscle to connective tissue. The model predicts significantly different contractile responses depending on the proportion of muscle to connective tissue in the remodelled airway. We find that radial and hoop-stress distributions in remodelled muscle layers are highly heterogenous with distinct regions of compression and tension. Such patterns of stress are likely to have important implications, from a mechano-transduction perspective, on contractility, short-term cytoskeletal adaptation and long-term airway remodelling in asthma.

Transient oscillatory force-length behavior of activated airway smooth muscle.

Airway smooth muscle (ASM) is cyclically stretched during breathing, even in the active state, yet the factors determining its dynamic force-length behavior remain incompletely understood. We developed a model of the activated ASM strip and compared its behavior to that observed in strips of rat trachealis muscle stimulated with methacholine. The model consists of a nonlinear viscoelastic element (Kelvin body) in series with a force generator obeying the Hill force-velocity relationship. Isometric force in the model is proportional to the number of bound crossbridges, the attachment of which follows first-order kinetics. Crossbridges detach at a rate proportional to the rate of change of muscle length. The model accurately accounts for the experimentally observed transient and steady-state oscillatory force-length behavior of both passive and activated ASM. However, the model does not predict the sustained decrement in isometric force seen when activated strips of ASM are subjected briefly to large stretches. We speculate that this force decrement reflects some mechanism unrelated to the cycling of crossbridges, and which may be involved in the reversal of bronchoconstriction induced by a deep inflation of the lungs in vivo.

Airway mechanics and methods used to visualize smooth muscle dynamics in vitro.

Contraction of airway smooth muscle (ASM) is regulated by the physiological, structural and mechanical environment in the lung. We review two in vitro techniques, lung slices and airway segment preparations, that enable in situ ASM contraction and airway narrowing to be visualized. Lung slices and airway segment approaches bridge a gap between cell culture and isolated ASM, and whole animal studies. Imaging techniques enable key upstream events involved in airway narrowing, such as ASM cell signalling and structural and mechanical events impinging on ASM, to be investigated.