Airway responsiveness depends on the diffusion rate of methacholine across the airway wall

During methacholine challenge tests of airway responsiveness, it is invariably assumed that the administered dose of agonist is accurately reflected in the dose that eventually reaches the airway smooth muscle (ASM). However, agonist must traverse a variety of tissue obstacles to reach the ASM, during which the agonist is subjected to both enzymatic breakdown and removal by the bronchial and pulmonary circulations. This raises the possibility that a significant fraction of the deposited agonist may never actually make it to the ASM. To understand the nature of this effect, we measured the time course of changes in airway resistance elicited by various durations of methacholine aerosol in mice. We fit to these data a computational model of a dynamically contracting airway responding to agonist that diffuses through an airway compartment, thereby obtaining rate constants that reflect the diffusive barrier to methacholine. We found that these barriers can contribute significantly to the time course of airway narrowing, raising the important possibility that alterations in the diffusive barrier presented by the airway wall may play a role in pathologically altered airway responsiveness.