Modeling pulmonary fibrosis progression caused by differential mechanical stretch

模拟差异机械拉伸引起的肺纤维化进展

• 批准号: 10677845
• 负责人: Ruogang Zhao
• 金额: $ 39.39万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677845
• 关键词: 3-Dimensional; Adenoviruses; Adopted; Affect; Alveolar; Alveolus; Animals; Area; Biomechanics; Bleomycin; Cell Culture Techniques; Cells; Cessation of life; Complex; Computer Models; Data; Development; Devices; Disease; Disease Progression; Engineering; Evolution; Fibrosis; Growth; Human; Image; In Vitro; Lung; Lung diseases; Lung fibrogenesis; Maps; Mechanics; Membrane; Microscopic; Modeling; Organ; Pattern; Population; Profibrotic signal; Progressive Disease; Pulmonary Fibrosis; Pulmonary Pathology; Rattus; Research; Research Personnel; Resolution; Sampling; Slice; Spatial Distribution; Stretching; Structure; Structure of parenchyma of lung; System; Techniques; Testing; Thick; Tissue Engineering; Tissue Model; Tissues; Transforming Growth Factor beta; Vacuum; animal tissue; cell growth; cell injury; cost; design; epithelial injury; fibrotic lung; flexibility; idiopathic pulmonary fibrosis; improved; in vitro Model; in vivo; innovation; lung injury; mechanotransduction; mouse model; preservation; reconstitution; scaffold; spatiotemporal; therapy development

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no cure. IPF development follows a unique pattern with fibrosis starting at the lung periphery and progressing toward the lung center. Little is known about the mechanism underlying the periphery-to-center progression of the disease. Recent studies suggest that the higher level of parenchymal expansion (strain) in the lung periphery serve to amplify and perpetuate the progression of fibrosis upon initial lung injury. Systematic inquiry of the spatiotemporal progression of pulmonary fibrosis has been challenging and cost prohibitive, because (1) correlative data on both lung pathology and lung mechanics are difficult to obtain due to the prolonged disease progression in human; (2) the most commonly used mouse model of bleomycin-induced fibrosis spontaneously resolves and therefore fails to fully reflect human fibrosis, and (3) current in vitro lung tissue models do not reproduce an in vivo-like strain gradient and the complex biomechanics existing in the native alveolar structure. The objective of this project is to understand the spatiotemporal relation between pulmonary fibrosis and mechanical stretch in the lung and develop a stretched engineered lung slice (ELS) model to study the multiscale biomechanical mechanism of differential stretch-induced spatial progression of pulmonary fibrosis. The main hypothesis is that the high level mechanical stretch at the lung periphery amplifies the pro-fibrotic signaling in injured lung cells, thus initiating fibrosis and perpetuating the periphery-to-center fibrosis progression in the lung. Recently, investigator’s team have adopted decellularization technique to create ELSs that support the long term growth of lung cells in structurally-persevered human lung scaffolds. To utilize the ELS in the study of the fibrosis progression, investigators plan to adopt a multiscale biomimicry strategy where the integration of ELS with a gradient stretching device allows macroscopic modelling of the differential strains existing at the lung periphery and lung center, and the preserved structure in the ELS allows microscopic modelling of the mechanical signal transduction and cellular injury existing at the single alveolus level. The aims include characterizing the spatiotemporal evolution of pulmonary fibrosis and mechanical stretch in both human and rat fibrotic lung samples, developing a differentially-stretched, ELS model to test how realistic strain gradients affect spatial progression of fibrosis upon epithelial injury, and understanding the multiscale biomechanical mechanism of stretch induced fibrosis initiation and progression. The combination of mechanical stretching and computational modeling with the lung slice model will substantially improve the utility of this underutilized model for lung disease research, thus greatly facilitating the research efforts in pulmonary fibrosis and improving the understanding of a major disease mechanism that is poorly examined in the past.

特发性肺纤维化（IPF）是一种无法治愈的进行性肺部疾病。指规数的发展遵循 独特的模式，纤维化开始于肺外周并向肺中心进展。之甚少 了解疾病从外周向中心进展的机制。最近的研究 表明肺周围较高水平的实质扩张（应变）有助于放大和 使初始肺损伤后的纤维化进程永久化。时空的系统探究 肺纤维化的进展一直是具有挑战性的和成本高昂的，因为（1）相关的数据， 肺病理学和肺力学都难以获得， 人;（2）最常用的博来霉素诱导的纤维化小鼠模型自发消退， 因此不能完全反映人类纤维化，和（3）目前的体外肺组织模型不能再现一个在肺组织中的纤维化。 活体样应变梯度和复杂的生物力学存在的天然牙槽结构。客观 本项目的主要目的是了解机械牵张与肺纤维化的时空关系 并建立了一个拉伸的工程肺切片（ELS）模型，以研究多尺度生物力学 差异牵张诱导肺纤维化空间进展的机制。主要的假设是 肺外周的高水平机械拉伸放大了受损肺中的促纤维化信号传导 细胞，从而引发纤维化并使肺中的外周至中心纤维化进展持续。最近， 研究人员的团队采用脱细胞技术来创建支持长期生长的ELSs 肺细胞在结构上保持不变的人肺支架上的生长。将ELS用于纤维化的研究 随着研究的进展，研究人员计划采用多尺度仿生策略，将ELS与 梯度拉伸装置允许对存在于肺外周的不同应变进行宏观建模 和肺中心，并且ELS中保存的结构允许机械信号的微观建模 转导和细胞损伤存在于单个肺泡水平。目标包括表征 人和大鼠肺纤维化及机械牵张时空演变 样品，开发一个差异拉伸，ELS模型，以测试如何现实的应变梯度影响空间 上皮损伤后纤维化的进展，并了解多尺度生物力学机制， 牵张诱导纤维化的发生和发展。机械拉伸和计算拉伸的结合 用肺切片模型建模将显著地改善这种未充分利用的模型对于肺的效用 疾病研究，从而极大地促进了肺纤维化的研究工作， 了解一种过去研究得很差的主要疾病机制。