Multiscale Interaction of Pulmonary Gas Flow and Lung Tissue Mechanics

描述（由申请人提供）：本研究的主要目的是应用基于图像的流体结构相互作用（FSI）技术来研究肺部气体流动与肺组织力学之间的多尺度相互作用所产生的机械力，及其在肺部疾病的分布和进展中的作用。推动这项工作的一个生物学假说是，肺部疾病改变机械力，从而改变应激介导的三磷酸腺苷核苷酸释放，扰乱胆周液（PCL）水稳态，削弱气道综合防御系统，形成恶性循环。在多学科的努力下，本提案寻求采用一种创新的系统生物学方法，将力学和细胞模型结合起来，模拟机械力从宏观到微观尺度的传递，并进一步转化为细胞水平的生化反应，以维持黏毛清除的PCL体积。为了实现目标和检验假设，我们提出以下具体目标。(1)研究气流诱导的剪切应力和气道壁组织应力在阻力最大的中央6代气道中的分布。重点将放在由于气道僵硬、气道狭窄和组织僵硬引起的应力变化上，特别是在正常、哮喘和肺气肿受试者中评估的上下叶分叉附近。(2)从PCL水位和钙离子浓度的区域分布以及人肺热湿热力学角度研究支气管上皮细胞对应激变化的生化反应。重点将放在由于上叶和下叶分叉附近的PCL体积耗竭或过度生产而导致的PCL水稳态偏离，并评估其对纤毛粘膜运输的影响。(3)通过我们的医学图像文件归档系统和模型存储库，与研究和临床社区共享本项目开发的数据库和模型。为了实现这些目标，我们将扩展现有的流动模型，通过图像配准辅助FSI来模拟气流和组织之间机械力的传递，从而包括肺组织力学。我们还将在现有的纤毛上皮细胞钙信号和跨膜离子和水通量模型中加入应力依赖的核苷酸模型。将流体结构（器官-组织）力学模型和上皮细胞模型与区域分布气道热力学相结合，预测健康和病变气道中PCL层深度和钙离子浓度的动态变化。多检测器行计算机断层扫描（MDCT）实验和细胞培养实验将进行模型改进和验证。

DESCRIPTION (provided by applicant): The broad objective of this research is to apply the image-based fluid-structure interaction (FSI) technique to study the mechanical force resulting from the multiscale interactions between pulmonary gas flow and lung tissue mechanics, and its role in the distribution and progression of lung disease. A biological hypothesis motivating this work is that lung diseases alter mechanical force, which then alters stress-mediated adenosine triphosphate nucleotide release, disturbs periciliary liquid (PCL) water homeostasis, and weakens the integrated airway defense system, forming a vicious cycle of events. In a multidisciplinary effort, this proposal seeks to adopt an innovative systems biology approach that integrates mechanics and cell models to model transmittal of mechanical force from macro to micro scales, and further translation to biochemical responses at cellular level to maintain the PCL volume for mucociliary clearance. To achieve the objective and test the hypothesis, we propose the following specific aims. (1) Study the distributions of airflow-induced shear stress and airway-wall tissue stress in the central 6 generations of airways where the maximum resistance occurs. The emphasis will be placed on alteration of stresses due to airway rigidity, airway narrowing, and tissue stiffness, especially near the bifurcations in both upper and lower lobes as assessed in normal, asthmatic and emphysema subjects. (2) Study the biochemical responses of bronchial epithelial cells to the alteration of stresses in terms of the regional distributions of PCL water level and calcium ion concentration together with thermodynamics for heat and moisture in the human lung. The emphasis will be placed on deviation from PCL water homeostasis due to depletion or over-production of PCL volume near the bifurcations in both upper and lower lobes, and assess its implication on mucociliary transport. (3) Share the databases and models developed for this project with research and clinical communities via our medical image file archive system and model repository. To achieve these aims, we will extend our existing flow model to include lung tissue mechanics via image-registration-assisted FSI to simulate transmittal of mechanical force between airflow and tissue. We will also incorporate a stress-dependent nucleotide model into our existing model for calcium signaling and transmembrane ion and water fluxes in the ciliated epithelial cell. The fluid-structure (organ- tissue) mechanics model and the epithelial cell model will be integrated with regionally distributed airway thermodynamics to predict dynamic changes in the depth of the PCL layer and calcium ion concentration in the healthy and diseased airways. Both multi-detector row computed tomography (MDCT) experiments and cell culture experiments will be performed for model refinement and validation.