CONNECTIVE TISSUE MECHANICS IN EMPHYSEMA AND FIBROSIS

描述（改编自申请人的摘要）：滞后 包括组织和表面膜的肺实质的性质是 肺组织阻力（Rt）的主要决定因素， 呼吸频率下的总肺阻力的组成部分。 在大多数肺 疾病时，Rt和肺组织弹性（Et）增加。 这些功能 变化总是伴随着肺泡壁的增厚。 最近 研究表明，Rt和Et的增加是由于 肺泡壁 然而，在纤维、细胞或 产生Rt和Et分子水平还远不清楚。 这些发现 导致他们制定了以下可检验的假设：1）主要的 实质组织阻力的部位是肺泡的纤维网络 壁，和2）Rt和Et的变化直接相关的改变， 纤维含量和结构。 他们指出，组织阻力与 粘性能量耗散，反过来，必须源于内部 齿槽内某些元素相对于彼此的运动 墙 这些元素是什么？ 呼吸时的肺泡壁 如何改变的组成， 肺泡壁改变这种运动以增加粘性能量耗散 和硬度？ 在这份提案中，他们打算澄清基本的 确定的弹性和滞后性能的机制， 实质及其在正常肺中的作用，在肺气肿和纤维化中， 主要影响结缔组织或胶原弹性蛋白的肺部疾病 光纤网络 他们的初步数据提供了直接的实验证据 纤维在应力松弛期间进行缓慢运动， 纤维是RT的重要贡献者。因此，他们建议测试肺 组织性质在三个不同的尺度：1）他们将进行整体 肺实验，以确定器官水平的变化的后果， 肺泡壁的组成，例如消化弹性蛋白纤维或 产生肺纤维化; 2）消除气道的影响， 表面活性剂，它们将对组织进行宏观力学测量 同时直接改变细胞外基质的组成 这将提供有关胶原蛋白和弹性蛋白的贡献的信息， 纤维网络和蛋白多糖基质的Rt和Et; 3）揭示 组织滞后行为的基本机制，他们 将在牙槽壁进行应力松弛测量， 通过免疫荧光观察发生在 单个胶原蛋白或弹性蛋白纤维的水平。 这些机械测量 将补充荧光标记纤维的图像分析 网络来量化肺泡壁组成的变化。 建议的研究将大大提高他们对 肺实质宏观流变学行为的起源， 创造一个机会，弥合器官水平功能之间的差距， 细胞外基质成分的生物物理特性。

DESCRIPTION (Adapted from the applicant's abstract): The hysteretic properties of lung parenchyma including tissue and surface film are the primary determinants of lung tissue resistance (Rt) which is a major component of total lung resistance at breathing frequencies. In most lung diseases, Rt and lung tissue elastance (Et) increase. These functional changes are invariably accompanied by thickening of alveolar walls. Recent studies suggest that increases in Rt and Et are due to thickening of alveolar walls. However, the actual mechanisms at the fiber, cellular or molecular level that produce Rt and Et are far from clear. These findings led them to formulate the following testable hypothesis: 1) The primary locus of parenchymal tissue resistance is the fiber network of the alveolar wall, and 2) changes in Rt and Et are directly related to alterations in fiber content and structure. They noted that tissue resistance is related to viscous energy dissipation which, in turn, must originate from internal motion of certain elements with respect to each other within the alveolar wall. What are those elements and what kind of motion takes place in the alveolar wall during breathing? How do alterations in the composition of the alveolar wall change this motion to increase viscous energy dissipation and stiffness? In this proposal, they intend to clarify the fundamental mechanisms that determine the elastic and hysteretic properties of the parenchyma and their role in the normal lung, in emphysema and fibrosis, two lung diseases that affect primarily the interstitium or the collagen-elastin fiber network. Their preliminary data provide direct experimental evidence that fibers carry out slow motion during stress relaxation implying that fibers are important contributors to Rt. Thus, they propose testing lung tissue properties at three different scales: 1) They will carry out whole lung experiments to identify organ level consequences of alterations in the composition of the alveolar wall such as digesting elastin fibers or producing pulmonary fibrosis; 2) To eliminate the influences of airways and surfactant, they will make macroscopic mechanical measurements on tissue strips while directly changing the composition of the extracellular matrix which will provide information on the contribution of collagen and elastin fiber network, and proteoglycan ground substance to Rt and Et; 3) To reveal the fundamental mechanism responsible for tissue hysteretic behavior, they will carry out stress relaxation measurements in the alveolar wall combined with immunofluorescent visualization of the dynamic events occurring at the level of a single collagen or elastin fiber. These mechanical measurements will be complemented with image analysis of the fluorescently labeled fiber network to quantify the alterations in the composition of the alveolar wall. The proposed research will greatly enhance their understanding of the origins of the macroscopic rheological behavior of lung parenchyma and create an opportunity to bridge the gap between the organ level function and the biophysical properties of the components of the extracellular matrix.