A multi-scale approach to airway hyperresponsiveness: from molecule to organ.
A multi-scale approach to airway hyperresponsiveness: from molecule to organ.
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DOI：
10.3389/fphys.2012.00191
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发表时间：
2012
影响因子：
4
通讯作者：
Sanderson MJ
中科院分区：
文献类型：
--
作者：
Lauzon AM;Bates JH;Donovan G;Tawhai M;Sneyd J;Sanderson MJ
气道高反应性 (AHR) 是哮喘的一个特征，涉及气道口径过度减小，是一种复杂的机制，反映了在大范围的长度和时间尺度上表现出来的多个过程。在一种极端情况下，分子相互作用决定了气道平滑肌 (ASM) 产生的力。另一方面，分支气道的空间分布收缩导致呼吸困难。同样，哮喘治疗在分子水平上发挥作用，而临床结果则由肺功能决定。这些极端事件与中等长度和时间范围内发生的事件联系在一起。因此，AHR 是一种新兴现象，它限制了我们对哮喘的理解，并混淆了在有限范围内解决生理机制的研究的解释。解决方案是集成多个尺度的实验和数学数据的模块化计算模型。这包括在分子尺度上，跨桥和闩锁状态循环期间肌动蛋白-肌球蛋白收缩蛋白的动力学和力产生；在细胞尺度上，调节 ASM 力产生的 Ca2+ 信号传导机制；在组织尺度上，收缩的 ASM 和相反的粘弹性组织之间作用的力决定气道变窄；在器官尺度上，ASM 收缩动力学的地形分布决定了肺的机械阻抗。在每个尺度上，模型都是通过理论和实验之间的迭代来构建的，以确定链接相邻尺度的参数。该模块化模型建立了在广泛范围内进行建模的算法，并提供了包含其他反应（例如炎症或治疗方案）的框架。目标是开发这种肺部模型，以便它能够预测支气管收缩并确定对 AHR 及其治疗影响最大的病理生理机制。
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, Ca2+ 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.
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影响因子：
3.8
作者：
Bates, Jason H. T.
通讯作者：
Bates, Jason H. T.
气道平滑肌松弛是由于CAMP介导的IP3受体抑制引起的Ca2+振荡频率的降低而导致的。
影响因子：
5.8
作者：
Bai, Y;Sanderson, MJ
通讯作者：
Sanderson, MJ
DOI：
10.1152/ajplung.00129.2005
发表时间：
2005-11-01
影响因子：
4.9
作者：
Bates, JHT;Lauzon, AM
通讯作者：
Lauzon, AM
影响因子：
3.3
作者：
Bates, Jason H. T.;Cojocaru, Ana;Lundblad, Lennart K. A.
通讯作者：
Lundblad, Lennart K. A.
DOI：
10.1152/ajplung.00095.2009
发表时间：
2009-08-01
影响因子：
4.9
作者：
Bates, J. H. T.;Bullimore, S. R.;Lauzon, A. -M.
通讯作者：
Lauzon, A. -M.