Asthma is a common disease affecting an increasing number of children throughout the world. In asthma, pulmonary airways narrow in response to contraction of surrounding smooth muscle. The precise nature of functional changes during an acute asthma attack is unclear. The tree structure of the pulmonary airways has been linked to complex behaviour in sudden airway narrowing and avalanche-like reopening. Here we present experimental evidence that bronchoconstriction leads to patchiness in lung ventilation, as well as a computational model that provides interpretation of the experimental data. Using positron emission tomography, we observe that bronchoconstricted asthmatics develop regions of poorly ventilated lung. Using the computational model we show that, even for uniform smooth muscle activation of a symmetric bronchial tree, the presence of minimal heterogeneity breaks the symmetry and leads to large clusters of poorly ventilated lung units. These clusters are generated by interaction of short- and long-range feedback mechanisms, which lead to catastrophic shifts similar to those linked to self-organized patchiness in nature. This work might have implications for the treatment of asthma, and might provide a model for studying diseases of other distributed organs.

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.

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.

Rationale: Bronchoconstriction in asthma leads to heterogeneous ventilation and the formation of large and contiguous ventilation defects in the lungs. However, the regional adaptations of pulmonary perfusion (Q ) to such ventilation defects have not been well studied. Methods: We used positron emission tomography to assess the intrapulmonary kinetics of intravenously infused tracer nitrogen-13 ( 13 NN), and measured the regional distributions of ventilation and perfusion in 11 patients with mild asthma. For each subject, the regional washout kinetics of 13 NN before and during methacholineinduced bronchoconstriction were analyzed. Two regions of interest (ROIs) were defined: one over a spatially contiguous area of high tracer retention (TR) during bronchoconstriction and a second one covering an area of similar size, showing minimal tracer retention (NR). Results: Both ROIs demonstrated heterogeneous washout kinetics, which could be described by a two-compartment model with fast and slow washout rates. We found a systematic reduction in regional Q to the TR ROI during bronchoconstriction and a variable and nonsignificant change in relative Q for NR regions. The reduction in regional Q was associated with an increase in regional gas content of the TR ROI, but its magnitude was greater than that anticipated solely by the change in regional lung inflation. Conclusion: During methacholine-induced bronchoconstriction, perfusion to ventilation defects are systematically reduced by a relative increase in regional pulmonary vascular resistance.Keywords: emission computed tomography; pulmonary gas exchange; vascular resistance; vasoconstriction; ventilation-perfusion ratio It is well established that severe heterogeneity of regional ventilation contributes significantly to gas exchange impairment in asthma. However, the extent to which regional pulmonary perfusion adapts to match changes in ventilation during an asthma attack is unknown. Evidence for severe heterogeneity of regional ventilation in patients with asthma has come from measurements with external scintillation counters (1, 2), single-photon emission computed tomography (CT) of Technegas (3), nuclear magnetic resonance imaging after a single-breath inhalation of hyperpolarized helium (4), and high-resolution CT (5-10). Most of these studies, however, did not quantify regional ventilation during normal breathing and did not evaluate the effect of bronchoconstriction on regional pulmonary perfusion.Changes in regional perfusion during bronchoconstriction (BC) have been measured using technetium ( 99m Tc)-labeled macroaggregated albumin (11,12). In one study, perfusion defects of segmental or smaller size were reported mainly at the periphery of middle or lower lung zones in children with asthma, despite normal chest X-rays, blood gases, and peak expiratory flows (13). That study, however, did not assess whether these perfusion defects corresponded to defects in ventilation. Another study assessed ventilation with krypton ( 81m Kr) gas and perfusion with 99m Tc ...