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 narrowing1,2 and avalanche-like reopening3,4. 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 nature5,6. This work might have implications for the treatment of asthma, and might provide a model for studying diseases of other distributed organs.

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Figure 1: Heterogeneity in bronchoconstriction of an asthmatic's lung.
Figure 2: Modelling of bronchoconstricted lungs.
Figure 3: Tidal volume-dependent hysteresis in regional ventilation distribution to terminal units.
Figure 4: Distributions of ventilation under three conditions.

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Acknowledgements

We are grateful to T. A. Wilson, K. M. Miller, E. Lowenstein, B. Suki, J. P. Butler, M. Reitkerk and J. J. Fredberg for their suggestions and comments during the preparation of the manuscript. J. A. Correia and W. M. Bucelewicz are thanked for their help with technical aspects of the tracer preparation. This work was funded by an NIH HLBI grant.Authors' contributions J.G.V. and T.W. contributed equally to the theoretical aspects of this work. All authors contributed to experimental components of this work.

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Correspondence to Jose G. Venegas.

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Supplementary information

Supplementary Methods S1

Details of PET imaging of Bronchoconstriction and the Model of Bronchoconstriction in an Airway Tree (PDF 134 kb)

Supplementary Video Legends S2

Legends to accompany the below Supplementary Videos. (PDF 46 kb)

Supplementary Video S3

Regional kinetics of the 13NN tracer in an asthmatic subject at baseline illustrates an almost complete removal of the tracer by the end of a washout period. (MPG 687 kb)

Supplementary Video S4

Regional kinetics of the 13NN tracer in an asthmatic subject during bronchoconstriction shows a substantially reduced washout from large contiguous 'ventilation defects'. (MPG 645 kb)

Supplementary Figure S5

Full set of PET images from an asthmatic subject during bronchoconstriction showing the residual tracer before and after deep inspiration. (PDF 317 kb)

Supplementary Video S6

Spatial distribution and histogram of terminal unit ventilation in the network model during a slow steady increase in smooth muscle relative activation from 0 to 1. (MPG 5997 kb)

Supplementary Figure S7

Complex dynamics of ventilation within the model during the simulation as a function of smooth muscle activation level. (PDF 611 kb)

Supplementary Figure S8

Fraction of clusters size and fraction of severely obstructed units as a function of tidal volume. (PDF 56 kb)

Supplementary Figure S9

Airway radius, normalized by the corresponding radius in relaxed conditions, versus generation number for each of the model's 12 generations. (PDF 334 kb)

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Venegas, J., Winkler, T., Musch, G. et al. Self-organized patchiness in asthma as a prelude to catastrophic shifts. Nature 434, 777–782 (2005). https://doi.org/10.1038/nature03490

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