Perturbed equilibria of myosin binding in airway smooth muscle and its implications in airway hyperresponsiveness and asthma

Abstract

In asthma, the key effector driving acute airway narrowing is thought to be airway smooth muscle (ASM); as the muscle surrounding the airways shortens, the airway lumen narrows. Airway hyperresponsiveness (AHR) - the excessive narrowing of the airways - is one of the cardinal features of asthma. Yet, the mechanism(s) regulating the airway lumenal radius, and perhaps the failure of these mechanisms to prevent excessive airway constriction, remains largely unexplained. This thesis shows that the regulation of ASM length corresponds to a dynamically equilibrated steady-state, not the static mechanical equilibrium that had been previously assumed. This dynamic steady state requires as an essential feature a continuous supply of external mechanical energy (derived from tidal lung inflations) that act to perturb the interactions of myosin with actin, drive the molecular state of the system far away from thermodynamic equilibrium, and bias the muscle toward lengthening. This mechanism leads naturally to the suggestion that excessive airway narrowing in asthma may be associated with the destabilization of that dynamic process and its resulting collapse back to static equilibrium. With this collapse the muscle undergoes a phase transition and virtually freezes at its static equilibrium length. This mechanism may help to elucidate several unexplained phenomena including the multi-factorial origins of AHR, how allergen sensitization leads to AHR, and the inability in asthma of deep inspiration to relax ASM.