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Nonlinear compliance modulates dynamic bronchoconstriction in a multiscale airway model.

ABSTRACT: The role of breathing and deep inspirations (DI) in modulating airway hyperresponsiveness remains poorly understood. In particular, DIs are potent bronchodilators of constricted airways in nonasthmatic subjects but not in asthmatic subjects. Additionally, length fluctuations (mimicking DIs) have been shown to reduce mean contractile force when applied to airway smooth muscle (ASM) cells and tissue strips. However, these observations are not recapitulated on application of transmural pressure (PTM) oscillations (that mimic tidal breathing and DIs) in isolated intact airways. To shed light on this paradox, we have developed a biomechanical model of the intact airway, accounting for strain-stiffening due to collagen recruitment (a large component of the extracellular matrix (ECM)), and dynamic actomyosin-driven force generation by ASM cells. In agreement with intact airway studies, our model shows that PTM fluctuations at particular mean transmural pressures can lead to only limited bronchodilation. However, our model predicts that moving the airway to a more compliant point on the static pressure-radius relationship (which may involve reducing mean PTM), before applying pressure fluctuations, can generate greater bronchodilation. This difference arises from competition between passive strain-stiffening of ECM and force generation by ASM yielding a highly nonlinear relationship between effective airway stiffness and PTM, which is modified by the presence of contractile agonist. Effectively, the airway at its most compliant may allow for greater strain to be transmitted to subcellular contractile machinery. The model predictions lead us to hypothesize that the maximum possible bronchodilation of an airway depends on its static compliance at the PTM about which the fluctuations are applied. We suggest the design of additional experimental protocols to test this hypothesis.

SUBMITTER: Hiorns JE

PROVIDER: S-EPMC4269780 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Nonlinear compliance modulates dynamic bronchoconstriction in a multiscale airway model.

Hiorns Jonathan E JE Jensen Oliver E OE Brook Bindi S BS

Biophysical journal 20141201 12

The role of breathing and deep inspirations (DI) in modulating airway hyperresponsiveness remains poorly understood. In particular, DIs are potent bronchodilators of constricted airways in nonasthmatic subjects but not in asthmatic subjects. Additionally, length fluctuations (mimicking DIs) have been shown to reduce mean contractile force when applied to airway smooth muscle (ASM) cells and tissue strips. However, these observations are not recapitulated on application of transmural pressure (PT ...[more]

PMID: 25517167

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Project description:BACKGROUND:Asthma exacerbations cause lung hyperinflation, elevation in load to inspiratory muscles, and decreased breathing capacity that, in severe cases, may lead to inspiratory muscle fatigue and respiratory failure. Hyperinflation has been attributed to a passive mechanical origin; a respiratory system time-constant too long for full exhalation. However, because the increase in volume is also concurrent with activation of inspiratory muscles during exhalation it is unclear whether hyperinflation in broncho-constriction is a passive phenomenon or is actively controlled to avoid airway closure. METHODS:Using CT scanning, we measured the distensibility of individual segmental airways relative to that of their surrounding parenchyma in seven subjects with asthma and nine healthy controls. With this data we tested whether the elevation of lung volume measured after methacholine (MCh) provocation was associated with airway narrowing, or to the volume required to preventing airway closure. We also tested whether the reduction in FVC post-MCh could be attributed to gas trapped behind closed segmental airways. FINDINGS:The changes in lung volume by MCh in subjects with and without asthma were inversely associated with their reduction in average airway lumen. This finding would be inconsistent with hyperinflation by passive elevation of airway resistance. In contrast, the change in volume of each subject was associated with the lung volume estimated to cause the closure of the least stable segmental airway of his/her lungs. In addition, the measured drop in FVC post MCh was associated with the estimated volume of gas trapped behind closed segmental airways at RV. CONCLUSIONS:Our data supports the concept that hyperinflation caused by MCh-induced bronchoconstriction is the result of an actively controlled process where parenchymal distending forces on airways are increased to counteract their closure. To our knowledge, this is the first imaging-based study that associates inter-subject differences in whole lung behavior with the interdependence between individual airways and their surrounding parenchyma.

Dataset Information

Nonlinear compliance modulates dynamic bronchoconstriction in a multiscale airway model.

Publications

Nonlinear compliance modulates dynamic bronchoconstriction in a multiscale airway model.

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