Airway Smooth Muscle And Airway Wall Coupled Dynamics

Primarily, asthma is a disease of reversible airway constriction which is characterized by airways that constrict too easily and too much. These processes are modulated via a layer of airway smooth muscle (ASM) which surrounds each airway in the lung, wherein its activation leads to airway narrowing and potentially, closure. As a result, understanding the interaction between the ASM and the airway wall is crucial to understanding the reversible airway obstruction central to asthma. Although cross-bridge theory is a well-studied representation of complex smooth muscle dynamics, and can be coupled to the airway wall, this comes at significant computational cost, even for isolated airways. Because many phenomena of interest in pulmonary physiology cannot be adequately understood by studying isolated airways, this presents a significant limitation.We present a distribution moment (DM) approximation for the coupled system consisting of the ASM and the airway wall. Specifically, we first derive a reduced DM system for the cross-bridge theory which capture the macroscopic characteristics of the original full ASM theory. We then study the validity of the reduced coupled system when the airway is subjected to periodic pressure oscillations and show that in most cases, the DM system is valid. We also explore the region of breakdown. These results show that in many situations within physiological ranges, the DM approximation provides an orders-of-magnitude reduction in computational complexity relative to the full cross-bridge-airway coupled system. Deep inspirations (DI) are a widely studied topic due to their varied effectiveness as a bronchodilator in asthmatic and non-asthmatic patients. Specifically, it is known to be effective at reversing bronchoconstriction in non-asthmatic patients but may fail to prevent bronchoconstriction in asthmatic patients. Inspired by a recent study on the effect of deep inspirations on the rate of re-narrowing of an isolated airway, we investigate whether latch-bridge dynamics of the cross-bridge theory, coupled with non-linear compliance of the airway wall, can fully account for the reported results. We develop and present length-and pressure-controlled protocols which mimic both the experiments performed in the study, as well as simulate in vivo conditions respectively. The protocols are modelled using the DM approximation and show qualitative agreement with the results reported by the experiments, suggesting that latch-bridge dynamics coupled with airway wall non-compliance is sufficient to explain these results. As a secondary study, we also show that the DM approximated method is a suitable method to further investigate DIs on isolated (or branched) airways, as it is both qualitatively and quantitatively similar to the full cross-bridge model under equivalent conditions, and is less computationally intensive than traditional methods. We also study clustered ventilation defects, which are a hallmark of asthma characterized by the emergence of spatially organised regions of hypo- and hyper-ventilated airways.These regions (clusters) can vary from event to event and as such are considered to be partially dynamic rather than purely structural. We investigate these defects by incorporating rich ASM dynamics to systems of symmetrically branched coupled airways via the DM method, and compare the qualitative and quantitative behaviour of this system to a full ASM model, as well as to a simplified ASM model. We study the distribution of clusters of closed airways as a result of randomly perturbed initial airway radii for increasing ASM activation at static pressures. Our results show that the inclusion of rich ASM dynamics via the DM approximation leads to clustering distributions that are qualitatively similar to the highly simplified model as well as to the full ASM model. We also show that the DM model is less computationally intensive for both large and small numbers of coupled branched airways, and suggests that this model represents a viable option for the inclusion of rich ASM dynamics in whole lung models in future studies.