Identifying airways responsible for heterogeneous ventilation and mechanical dysfunction in asthma: an image functional modeling approach.

We present an image functional modeling approach, which synthesizes imaging and mechanical data with anatomically explicit computational models. This approach is utilized to identify the relative importance of small and large airways in the simultaneous deterioration of mechanical function and ventilation in asthma. Positron emission tomographic (PET) images provide the spatial distribution and relative extent of ventilation defects in asthmatic subjects postbronchoconstriction. We also measured lung resistance and elastance from 0.15 to 8 Hz. The first step in image functional modeling involves mapping ventilation three-dimensional images to the computational model and identifying the largest sized airways of the model that, if selectively constricted, could precisely match the size and anatomic location of ventilation defects imaged by PET. In data from six asthmatic subjects, these airways had diameters <2.39 mm and mostly <0.44 mm. After isolating and effectively closing airways in the model associated with these ventilation defects, we imposed constriction with various means and standard deviations to the remaining airways to match the measured lung resistance and elastance from the same subject. Our results show that matching both the degree of mechanical impairment and the size and location of the PET ventilation defects requires either constriction of airways <2.4 mm alone, or a simultaneous constriction of small and large airways, but not just large airways alone. Also, whereas larger airway constriction may contribute to mechanical dysfunction during asthma, degradation in ventilation function requires heterogeneous distribution of near closures confined to small airways.

Tissue heterogeneity in the mouse lung: effects of elastase treatment.

We developed a network model in an attempt to characterize heterogeneity of tissue elasticity of the lung. The model includes a parallel set of pathways, each consisting of an airway resistance, an airway inertance, and a tissue element connected in series. The airway resistance, airway inertance, and the hysteresivity of the tissue elements were the same in each pathway, whereas the tissue elastance (H) followed a hyperbolic distribution between a minimum and maximum. To test the model, we measured the input impedance of the respiratory system of ventilated normal and emphysematous C57BL/6 mice in closed chest condition at four levels of positive end-expiratory pressures. Mild emphysema was developed by nebulized porcine pancreatic elastase (PPE) (30 IU/day x 6 days). Respiratory mechanics were studied 3 wk following the initial treatment. The model significantly improved the fitting error compared with a single-compartment model. The PPE treatment was associated with an increase in mean alveolar diameter and a decrease in minimum, maximum, and mean H. The coefficient of variation of H was significantly larger in emphysema (40%) than that in control (32%). These results indicate that PPE treatment resulted in increased time-constant inequalities associated with a wider distribution of H. The heterogeneity of alveolar size (diameters and area) was also larger in emphysema, suggesting that the model-based tissue elastance heterogeneity may reflect the underlying heterogeneity of the alveolar structure.

Relation between structure, function, and imaging in a three-dimensional model of the lung.

Previous studies have reported morphometric models to predict function relations in the lung. These models, however, are not anatomically explicit. We have advanced a three-dimensional airway tree model to relate dynamic lung function to alterations in structure, particularly when constriction patterns are imposed heterogeneously inspecific anatomic locations. First we predicted the sensitivity of dynamic lung resistance and elastance (RL and EL) to explicit forms of potential constriction patterns. Simulations show that severe and heterogeneous peripheral airway constriction confined to a single region in the lung (apex, mid, or base) will not produce substantial alterations in whole lung properties as measured from the airway opening. Conversely, when measured RL and EL are abnormal, it is likely that significant (but not necessarily homogeneous) constriction has occurred throughout the entire airway tree. We also introduce the concept of image-assisted modeling. Here positron emission tomographic imaging data sensitive to ventilation heterogeneity is synthesized with RL and EL data to help identify which airway constriction conditions could be consistent with both data sets. An ultimate goal would be personalized predictions.