Bronchospasm and its biophysical basis in airway smooth muscle

Abstract

Airways hyperresponsiveness is a cardinal feature of asthma but remains unexplained. In asthma, the airway smooth muscle cell is the key end-effector of bronchospasm and acute airway narrowing, but in just the past five years our understanding of the relationship of responsiveness to muscle biophysics has dramatically changed. It has become well established, for example, that muscle length is equilibrated dynamically rather than statically, and that non-classical features of muscle biophysics come to the forefront, including unanticipated interactions between the muscle and its time-varying load, as well as the ability of the muscle cell to adapt rapidly to changes in its dynamic microenvironment. These newly discovered phenomena have been described empirically, but a mechanistic basis to explain them is only beginning to emerge.

Figure 1

A computational result showing airway length (top) and airway resistance (bottom) as a function of agonist concentration for a tenth generation airway [151]. The cases shown depict airways from a normal, an asthmatic and a COPD lung. In this computation, the effects of tidal breathing and deep inspirations (6/minute) upon myosin binding dynamics are taken into account explicitly [151]. As explained in the text, such an airway exhibits both hyperreactivity and hypersensitivity.

Figure 2

The perturbed equilibrium hypothesis connects phenotypes that were largely unexplained and had been thought to be essentially unrelated. Reduced force fluctuations and/or increased bridge cycling rates allow airway smooth muscle to more nearly approach a static equilibrium of myosin binding (latch) and the frozen state. Airway hyperresponsiveness phenotypes shown in blue correspond to circumstances in which the airway and airway smooth muscle might be normal but there is a problem with the respiratory pump, i.e., the muscles of the chest wall. Those shown purples correspond to phenotypes in which the airway smooth muscle may be normal, but there is a problem in the mechanical coupling between the respiratory pump and the myosin motor. Finally, those shown in green correspond to phenotypes in which the problem may be at the level of the myosin motor itself. At that level, the rate of bridge cycling is thought to be influenced by its isoform, the amount of myosin light chain kinase, caldesmon, calponin, Rho-kinase and other factors.