Self-organized patchiness in asthma as a prelude to catastrophic shifts

Abstract

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.

Airway Bistability Is Modulated by Smooth Muscle Dynamics and Length-Tension Characteristics

“…We also extrapolated our model results to consider the potential implications of ASM-modulated airway opening/ closing transitions to coupled airway models, such as the formation of clustered ventilation defects (e.g., Venegas et al (6) and Donovan and Kritter (7)). The qualitative features of these curves suggest a greater propensity toward more modest airway narrowing, rather than effective closure, than might have been expected.…”

“…If the parameters are such that these curves have multiple intersections, then multiple (static) equilibria are possible. Because much of the physiological range of parameter space does allow multiple equilibria, this bistability has often been used to explain the occurrence of ventilation heterogeneity and clustered ventilation defects (6,7). However, these largely static representations contain incomplete information about how these states may be modulated by ASM dynamics.…”

“…There are several distinct, yet related, ideas: static bistability, either in an isolated airway (1) or in a terminal airway unit with coupled parenchymal tethering (2); dynamic coupling of the airway with airway smooth muscle (3)(4)(5); and mechanisms by which spatial organization of airway closure or near closure may lead to clustered ventilation defects (6,7). All are interrelated, but as of yet there is no integrated synthesis of all three mechanisms.…”

“…This suggests, on the whole, that individual airways may be more susceptible to narrowing than to closure; if so, this could have important implications for models that rely on the open-closed transitions (or at least functional closure) to drive clustered ventilation defects (6,7).…”

Comparison of generic and subject-specific models for simulation of pulmonary perfusion and forced expiration

“…This can partially be addressed by using regular airway asymmetry, as in Polak & Lutchen [35]; however, this does not provide a link to spatial locations of pathology, and the ability to customize the model to different subjects is limited. Recent imaging [36][37][38] and modelling [39,40] studies have highlighted the importance of regional differences in lung structure and function in asthma, suggesting that 'clustering' of airway closure is important in developing ventilation defects. It is unknown whether the location and magnitude of this clustering is important in interpreting forced expiration.…”