Complex airway behavior and paradoxical responses to bronchoprovocation

Abstract

Heterogeneity of airway constriction and regional ventilation in asthma are commonly studied under the paradigm that each airway's response is independent from other airways. However, some paradoxical effects and contradictions in recent experimental and theoretical findings suggest that considering interactions among serial and parallel airways may be necessary. To examine airway behavior in a bronchial tree with 12 generations, we used an integrative model of bronchoconstriction, including for each airway the effects of pressure, tethering forces, and smooth muscle forces modulated by tidal stretching during breathing. We introduced a relative smooth muscle activation factor (Tr) to simulate increasing and decreasing levels of activation. At low levels of Tr, the model exhibited uniform ventilation and homogeneous airway narrowing. But as Tr reached a critical level, the airway behavior suddenly changed to a dual response with a combination of constriction and dilation. Ventilation decreased dramatically in a group of terminal units but increased in the rest. A local increase of Tr in a single central airway resulted in full closure, while no central airway closed under global elevation of Tr. Lung volume affected the response to both local and global stimulation. Compared with imaging data for local and global stimuli, as well as for the time course of airway lumen caliber during bronchoconstriction recovery, the model predictions were similar. The results illustrate the relevance of dynamic interactions among serial and parallel pathways in airway interdependence, which may be critical for the understanding of pathological conditions in asthma.