Mitigation of airways responsiveness by deep inflation of the lung.

Stretching activated strips of airway smooth muscle (ASM) significantly affects both active force and stiffness due to a temporary reduction of the proportion of cycling myosin cross bridges that are bound to their actin binding sites. For the same reason, stretch applied to ASM in situ by a deep inflation (DI) of the lungs is one of the most potent means of reversing bronchoconstriction. When the DI is sufficiently large, however, and is applied while bronchoconstriction is in the process of developing, the subsequent depression in airway resistance is more persistent than can be attributed simply to temporary detachment of ASM cross bridges. In the present study, we use a computational model to demonstrate that this DI-induced ablation of airway responsiveness can be explained by a dose-dependent reduction in the number of cross bridges available to bind to actin when the ASM in the airway wall is stretched above a critical threshold strain and that this disruption of the contractile apparatus recovers over an order of magnitude longer time scale than that of the simple reattachment of unbound cross bridges. NEW & NOTEWORTHY The mechanisms by which deep inflation of the lung reverse bronchoconstriction and affect subsequent airway responsiveness have important potential implications for asthma, yet remain controversial. This study uses computational modeling to posit a mechanism by which sufficiently vigorous inflations applied during active bronchoconstriction not only transiently reverse bronchoconstriction, but also reduce subsequent airways responsiveness for a period of time. Fitting the model to published data in mice supports this notion.