Multiscale Interaction of Pulmonary Gas Flow and Lung Tissue Mechanics

描述(申请人提供)：这项研究的广泛目标是应用基于图像的流体-结构相互作用(FSI)技术来研究肺气流与肺组织力学多尺度相互作用所产生的机械力，及其在肺部疾病分布和发展中的作用。支持这项工作的生物学假说是，肺部疾病改变机械力，机械力进而改变应激介导的三磷酸腺苷核苷酸释放，扰乱睫状液(PCL)水稳态，削弱综合呼吸道防御系统，形成恶性循环。在一项多学科的努力中，该建议寻求采用一种创新的系统生物学方法，将力学和细胞模型相结合来模拟机械力从宏观到微观的传递，并进一步转化为细胞水平的生化反应，以维持PCL体积以进行粘液纤毛清除。为了实现这一目标并检验假设，我们提出了以下具体目标。(1)研究气流诱导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，特别是在正常、哮喘和肺气肿受试者中评估的上叶和下叶分叉附近。(2)从肺内PCL水位和钙离子浓度的区域分布及热湿热力学等方面研究了人肺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PCL体积耗尽或过度产生而偏离PCL水平衡的情况，并评估其对粘液纤毛运输的影响。(3)通过我们的医学图像档案系统和模型库，与研究和临床社区共享为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的机械力传递，从而包括肺组织力学。我们还将把应激依赖的核苷酸模型结合到我们现有的模型中，以研究纤毛上皮细胞中钙信号和跨膜离子和水通量。流体-结构(器官-组织)力学模型和上皮细胞模型将与区域分布的呼吸道热力学相结合，以预测健康和患病呼吸道中PCL层深度和钙离子浓度的动态变化。将进行多探测器行计算机层析成像(MDCT)实验和细胞培养实验，以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.