Abstract:
:Airway hyperresponsiveness (AHR), a characteristic of asthma that involves an excessive reduction in airway caliber, is a complex mechanism reflecting multiple processes that manifest over a large range of length and time scales. At one extreme, molecular interactions determine the force generated by airway smooth muscle (ASM). At the other, the spatially distributed constriction of the branching airways leads to breathing difficulties. Similarly, asthma therapies act at the molecular scale while clinical outcomes are determined by lung function. These extremes are linked by events operating over intermediate scales of length and time. Thus, AHR is an emergent phenomenon that limits our understanding of asthma and confounds the interpretation of studies that address physiological mechanisms over a limited range of scales. A solution is a modular computational model that integrates experimental and mathematical data from multiple scales. This includes, at the molecular scale, kinetics, and force production of actin-myosin contractile proteins during cross-bridge and latch-state cycling; at the cellular scale, Ca(2+) signaling mechanisms that regulate ASM force production; at the tissue scale, forces acting between contracting ASM and opposing viscoelastic tissue that determine airway narrowing; at the organ scale, the topographic distribution of ASM contraction dynamics that determine mechanical impedance of the lung. At each scale, models are constructed with iterations between theory and experimentation to identify the parameters that link adjacent scales. This modular model establishes algorithms for modeling over a wide range of scales and provides a framework for the inclusion of other responses such as inflammation or therapeutic regimes. The goal is to develop this lung model so that it can make predictions about bronchoconstriction and identify the pathophysiologic mechanisms having the greatest impact on AHR and its therapy.
journal_name
Front Physioljournal_title
Frontiers in physiologyauthors
Lauzon AM,Bates JH,Donovan G,Tawhai M,Sneyd J,Sanderson MJdoi
10.3389/fphys.2012.00191subject
Has Abstractpub_date
2012-06-11 00:00:00pages
191issn
1664-042Xjournal_volume
3pub_type
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pub_type: 杂志文章
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journal_title:Frontiers in physiology
pub_type: 杂志文章
doi:10.3389/fphys.2019.00510
更新日期:2019-05-07 00:00:00
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pub_type: 杂志文章
doi:10.3389/fphys.2018.01027
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journal_title:Frontiers in physiology
pub_type: 杂志文章
doi:10.3389/fphys.2018.01237
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journal_title:Frontiers in physiology
pub_type: 杂志文章
doi:10.3389/fphys.2017.00791
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journal_title:Frontiers in physiology
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
doi:10.3389/fphys.2018.00175
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pub_type: 杂志文章
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