Remodeling of the airway smooth muscle cell

急性呼吸道狭窄的终末效应者是气道平滑肌细胞。ASM细胞有一个 处于持续重塑状态的细胞骨架，这种重塑现在被认为是一种主要的 导致呼吸道过度狭窄的因素，这是哮喘的一个主要特征。为了解释 这种重塑的程度和进展速度，在这里我们提供了一个新的机制假说。 CSK重建的速度变化很大；根据情况，在相同的情况下 肌肉它可以在短到几天、几小时甚至几分钟的时间尺度上完成。我们已经在 最近发表的文献表明，平滑肌重塑的程度、进展的速度以及 驱动它的机制似乎都符合深能井中分子捕获的框架。 在有效基质温度的驱动下，分子跳出这些势垒。这个框架是 简单，吸引人，符合所有已发表的观察结果；例如，下面的面板说明了组织 当矩阵更热(即，更高)时，ASM条带确实会进行更多和更快的重塑 x)。但支持这一框架及其合理性的论点完全是事后的；没有 例外情况是，支持证据是间接的和相关的。这项研究旨在 提供支持或反驳该框架的可行性的机制基础。 该假说预言：从一个亚稳态到间歇性纳米尺度跃迁的存在 从另一种状态到另一种状态；CSK向更稳定的微构型的极缓慢演化(物理老化)； 通过施加大到足以克服能量的机械应力来重置这种进化 障碍，并使系统达到新的微配置(恢复活力)。目标1专注于蜂窝网络 水平；它的设计是为了测试细胞在生理条件下的生存、衰老和恢复活力。 机械加载。目标2侧重于分子水平；它的设计是为了测试分子- 测量跳数并描述驱动这些跳数的分子作用力。目标3整合了这些层次；它 旨在将衰老、恢复活力和跳跃联系在一起；它建议建立这些结构 这个年龄和返老还童是通过跳跃来重塑的。 Layer总结：细胞重新排列其内部骨架分子的能力起着重要的作用 在哮喘的呼吸道狭窄、血管疾病的血管狭窄和癌症的细胞侵袭中的作用。这里 我们调查了一种不同的方式来理解这种基本的重排过程可能是如何工作的。

The end-effector of acute airway narrowing is the airway smooth muscle (ASM) cell. The ASM cell has a cytoskeleton that is in a continuous state of remodeling, and this remodeling is now thought to be a major factor contributing to the excessive airway narrowing that is a cardinal feature of asthma. To explain the extent of this remodeling and its rate of progression, here we offer a novel mechanistic hypothesis. CSK remodeling proceeds at a rate that varies dramatically; depending upon circumstances, in the same muscle it can be completed on time scales as short as days, hours, or even minutes. We have argued in recent publications that the extent of smooth muscle remodeling, the rate at which it progresses, and the mechanisms that drive it, all appear to fit within the framework of molecular trapping in deep energy wells and molecular hopping out of those wells driven by an effective matrix temperature. This framework is simple, attractive, and fits all published observations; for example, the panels below illustrate at the tissue level that the ASM strip does indeed remodel more and remodel faster while the matrix is "hotter" (i.e., higher x). But the arguments in favour of this framework and its plausibility have been entirely post hoc; without exception the supporting evidence has been circumstantial and correlative. This research is designed to provide the mechanistic basis that would support or refute the tenability of that framework. The hypothesis predicts the existence of: intermittent nano-scale hopping transitions from one metastable state to another; extremely slowly evolution of the CSK into more stable microconfigurations (physical aging); resetting of that evolution by imposed mechanical stresses that are large enough to overcomeenergy barriers and bring the system to a new microconfiguration (rejuvenation). Aim 1 focuses on the cellular level; it is designed to test the existence aging and rejuvenation in cells subjected to physiological mechanical loading. Aim 2 focuses on the molecular level; it is designed to test the existence of molecular- scale hops and to characterize the molecular forces that drive those hops. Aim 3 integrates these levels; it is designed to link together aging, rejuvenation, and hopping; it proposes to establish that those structures that age and rejuvenate are the very same ones that remodel by hopping. Lay summary: The ability of the cell to rearrange the molecules of its internal skeleton plays an important role in airway narrowing in asthma, vessel narrowing in vascular disease, and cell invasion in cancer. Here we investigate a different way of understanding how this basic rearrangement process might work.