CONNECTIVE TISSUE MECHANICS IN EMPHYSEMA AND FIBROSIS

描述(改编自申请者的摘要)：迟滞 肺实质包括组织和表面膜的特性是 肺组织阻力(RT)的主要决定因素是 呼吸频率时的总肺阻力分量。在大多数肺中 疾病、RT和肺组织弹性(ET)增加。这些功能 改变总是伴随着肺泡壁的增厚。近期 研究表明，RT和ET的增加是由于血管增厚 肺泡壁。然而，纤维、细胞或 RT和ET产生的分子水平还远不清楚。这些发现 导致他们提出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 2)RT和ET的变化与血管的改变直接相关。 纤维含量和结构。他们指出，组织抵抗力与 粘性能量耗散，而粘性能量耗散又必须来自内部 某些元素在肺泡内相对于彼此的运动 墙。这些元素是什么？在宇宙中发生什么样的运动 呼吸时的肺泡壁？构成上的变化是如何 肺泡壁改变了这一运动以增加粘性能量耗散。 那僵硬呢？在这项提案中，他们打算澄清基本的 确定结构的弹性和滞回特性的机制 实质及其在正常肺、肺气肿和纤维化中的作用 主要影响间质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 纤维在应力松弛过程中进行慢动作，这意味着 纤维是rt的重要组成部分，因此，他们建议对肺进行检测。 三种不同尺度的组织特性：1)它们将执行完整的 肺实验，以确定器官水平的变化的后果 肺泡壁的成分，如消化弹性蛋白纤维或 产生肺纤维化；2)消除呼吸道和肺纤维化的影响 表面活性物质，他们将对组织进行宏观力学测量 直接改变细胞外基质的组成 这将提供关于胶原和弹性蛋白的贡献的信息 纤维网络，和蛋白多糖基质，以RT和ET；3)揭示 导致组织迟滞行为的基本机制，他们 将在牙槽壁联合进行应力松弛测量 通过免疫荧光可视化发生在 单一胶原蛋白或弹性蛋白纤维的水平。这些机械测量 将与荧光标记的纤维的图像分析相补充 以量化肺泡壁成分的变化。 拟议的研究将大大加深他们对 肺实质和肺组织宏观流变性的起源 创造机会弥合器官水平功能和 细胞外基质成分的生物物理性质。

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.