FACTORS DETERMINING HYPERREPSONSIVENESS FOR INTACT AIRWAYS

决定完整气道高反应性的因素

基本信息

项目摘要

DESCRIPTION (provided by applicant): What role does the airway smooth muscle (ASM) play in producing the asthmatic phenotype of airway hyperresponsiveness (AHR)? A plethora of studies confirm that length oscillations of isolated ASM can modulate and mitigate its net response to an agonist. Two related hypotheses at the molecular level have emerged to explain isolated ASM findings, namely that the normal responses to stretch arise from perturbed equilibrium of actin-myosin crossbridges and/or cytoskeletal fluidization of the ASM cell. However, a gap exists in bridging molecular level hypotheses from isolated ASM studies to actual AHR for an intact airway as it constricts in three-dimensions. Many important interactions occur within an intact airway's extracellular matrix (ECM) that can impact ASM contractility and hence airway constriction in situ. We have developed a unique ultrasound imaging-based system to dynamically probe intact airways. Here, the ASM is in its natural geometric state embedded within the airway wall's ECM, and the airway is exposed to physiologically relevant transmural pressure (Ptm) fluctuations. This system allows for concurrent real-time measurements of luminal diameter and wall thickness over the full length of an intact airway during any physiological Ptm fluctuations and/or induced constriction. These measurements allow us to calculate an extensive set of macroscopic mechanical properties of the intact airway system. We can also apply biochemical and histological approaches to examine the microscopic properties of the ASM cells and ECM fibers. Jointly, these preliminary data suggest in intact airways, Ptm variations may invoke cellular mechanisms of crossbridge detachment and/or actin de-polymerization (perhaps associated with cytoskeletal fluidization) but without necessarily resulting in airway dilation. Based on this, we propose to test the following hypothesis: HYPOTHESIS: In the intact airway system, transmural pressure variations during physiological breathing are insufficient to attenuate responsiveness because the mechanical properties of the airway wall's ECM prevent the effective disruption of ASM crossbridge cycling and actin polymerization. Corollary: In vivo, AHR in asthma cannot be explained simply as the inability to properly strain the ASM. Aim 1: To determine the contribution of dynamic Ptm variations to the responsiveness of intact airways. Aim 2: To determine the intra- and extracellular consequences of dynamic Ptm variations on intact airways. Aim 3: To determine how airway wall structural constituents and ASM cellular processes impact the responsiveness of intact airways exposed to dynamic transmural pressure variations. This proposal will address the crucial questions of if and how mechanisms associated with ASM contraction in isolation are relevant in a dynamic and complex intact airway system and, hence, relevant in modulating airway responsiveness. Our proposal represents an essential step to understand mechanisms relevant to airway hyperresponsiveness. PUBLIC HEALTH RELEVANCE: Asthma treatments are designed to target the smooth muscle, or inflammation, or airway wall remodeling, or some combination thereof; what works "best" for some subjects may be minimally effective in another. Our results will have a significant impact on interpreting previous and future studies based on isolated ASM strips and ASM cell cultures. Finally, we also expect that our results will eventually become useful in the treatment of asthmatic patients because we will provide a link between cellular processes and airway function, and hence symptoms.
描述(由申请人提供):气道平滑肌(ASM)在产生气道高反应性(AHR)的哮喘表型中发挥什么作用?大量研究证实,孤立 ASM 的长度振荡可以调节和减轻其对激动剂的净反应。分子水平上的两个相关假设已经出现,可以解释孤立的 ASM 发现,即对拉伸的正常反应源于肌动蛋白-肌球蛋白跨桥和/或 ASM 细胞的细胞骨架流体化的扰动平衡。然而,由于完整气道在三维上收缩,因此从孤立的 ASM 研究到实际 AHR 的分子水平假设之间存在差距。许多重要的相互作用发生在完整气道的细胞外基质 (ECM) 内,这些相互作用会影响 ASM 收缩性,从而影响气道原位收缩。我们开发了一种独特的基于超声成像的系统来动态探测完整的气道。在这里,ASM 处于嵌入气道壁 ECM 内的自然几何状态,并且气道暴露于生理相关的跨壁压力 (Ptm) 波动。该系统允许在任何生理 Ptm 波动和/或诱导收缩期间同时实时测量完整气道全长的管腔直径和壁厚。这些测量使我们能够计算完整气道系统的一系列广泛的宏观机械特性。我们还可以应用生化和组织学方法来检查 ASM 细胞和 ECM 纤维的微观特性。总之,这些初步数据表明,在完整的气道中,Ptm 变化可能会引发横桥脱离和/或肌动蛋白解聚的细胞机制(可能与细胞骨架流态化有关),但不一定导致气道扩张。基于此,我们建议检验以下假设: 假设:在完整的气道系统中,生理呼吸期间的跨壁压力变化不足以减弱反应性,因为气道壁 ECM 的机械特性阻止了 ASM 跨桥循环和肌动蛋白聚合的有效破坏。推论:在体内,哮喘中的 AHR 不能简单地解释为无法正确拉紧 ASM。目标 1:确定动态 Ptm 变化对完整气道反应性的贡献。目标 2:确定动态 Ptm 变化对完整气道的细胞内和细胞外影响。目标 3:确定气道壁结构成分和 ASM 细胞过程如何影响暴露于动态跨壁压力变化的完整气道的反应性。该提案将解决与 ASM 孤立收缩相关的机制是否以及如何与动态且复杂的完整气道系统相关的关键问题,从而与调节气道反应性相关。我们的建议代表了理解与气道高反应性相关机制的重要一步。 公共卫生相关性:哮喘治疗旨在针对平滑肌、炎症、气道壁重塑或其中的某种组合;对某些科目“最好”的方法可能对另一些科目效果甚微。我们的结果将对解释先前和未来基于分离的 ASM 条带和 ASM 细胞培养物的研究产生重大影响。最后,我们还期望我们的结果最终将有助于治疗哮喘患者,因为我们将提供细胞过程和气道功能以及症状之间的联系。

项目成果

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KENNETH R LUTCHEN其他文献

KENNETH R LUTCHEN的其他文献

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{{ truncateString('KENNETH R LUTCHEN', 18)}}的其他基金

FACTORS DETERMINING HYPERREPSONSIVENESS FOR INTACT AIRWAYS
决定完整气道高反应性的因素
  • 批准号:
    8049611
  • 财政年份:
    2010
  • 资助金额:
    $ 48.83万
  • 项目类别:
FACTORS DETERMINING HYPERREPSONSIVENESS FOR INTACT AIRWAYS
决定完整气道高反应性的因素
  • 批准号:
    7889840
  • 财政年份:
    2010
  • 资助金额:
    $ 48.83万
  • 项目类别:
FACTORS DETERMINING HYPERREPSONSIVENESS FOR INTACT AIRWAYS
决定完整气道高反应性的因素
  • 批准号:
    8435547
  • 财政年份:
    2010
  • 资助金额:
    $ 48.83万
  • 项目类别:
Airway Reactivity and Heterogeneity in Asthma
哮喘的气道反应性和异质性
  • 批准号:
    6864355
  • 财政年份:
    2005
  • 资助金额:
    $ 48.83万
  • 项目类别:
Airway Reactivity and Heterogeneity in Asthma
哮喘的气道反应性和异质性
  • 批准号:
    7371938
  • 财政年份:
    2005
  • 资助金额:
    $ 48.83万
  • 项目类别:
Airway Reactivity and Heterogeneity in Asthma
哮喘的气道反应性和异质性
  • 批准号:
    7017727
  • 财政年份:
    2005
  • 资助金额:
    $ 48.83万
  • 项目类别:
Airway Reactivity and Heterogeneity in Asthma
哮喘的气道反应性和异质性
  • 批准号:
    7172948
  • 财政年份:
    2005
  • 资助金额:
    $ 48.83万
  • 项目类别:
TRAINING PROGRAM IN QUANTITATIVE BIOLOGY AND PHYSIOLOGY
定量生物学和生理学培训计划
  • 批准号:
    6313887
  • 财政年份:
    2001
  • 资助金额:
    $ 48.83万
  • 项目类别:
TRAINING PROGRAM IN QUANTITATIVE BIOLOGY AND PHYSIOLOGY
定量生物学和生理学培训计划
  • 批准号:
    6628730
  • 财政年份:
    2001
  • 资助金额:
    $ 48.83万
  • 项目类别:
TRAINING PROGRAM IN QUANTITATIVE BIOLOGY AND PHYSIOLOGY
定量生物学和生理学培训计划
  • 批准号:
    6919142
  • 财政年份:
    2001
  • 资助金额:
    $ 48.83万
  • 项目类别:

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