Role of Nonlinear Serial Elasticity on Airway Smooth Muscle Contraction

Abstract

Both the elevated shortening velocity and maximal shortening capacity of airway smooth muscle (ASM) in asthmatic airways have been associated with airway hyperresponsiveness, even though the isometric force-generating capacity of the muscle is the same as in normal airways. This paradox may be partly explained by the relaxing role of tidal breathing, which is associated with perturbed equilibria of myosin binding. We have developed a theoretical model of airway narrowing to quantitatively assess how and in what degree the observed alterations in ASM contractility and nonlinear ASM serial elasticity (SE) can account for hyperresponsiveness in asthma. The model includes the elasticity and geometry of the lungs, ASM contractility, and the dynamics of breathing. The airway caliber, proportional to ASM length, is dynamically determined by the balance between the airway wall reaction force (AWRF) and ASM contractile force. AWRF depends on the instantaneous difference between pleural pressure and airway pressure at each generation of Weibel's symmetrical bronchial tree, elasticity and geometry of the airway wall, tethering of the airway to the lung parenchyma, and the state of lung inflation. ASM contractile force depends on myosin binding kinetics and the level of ASM activation. From equliriated ASM length the airway resistance is calculated. The model enables simulation of breathing in normal and asthmatic airways exposed to an increasing dose of spasmogen. Increasing the dose causes a contraction of the ASM, narrowing of the airways, and an exponential increase airway resistance. We show that an airway with asthmatic or sensitized muscle (increased level of myosin LC20 phosphorylation, by 30-50%) narrows faster and significantly more than a normal airway. These results lead to a plausible mechanism by which the rate of bridge cycling and its regulation may account for airway excessive narrowing in asthma.