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) 是一种进行性肺部疾病，无法治愈。 纤维化从肺周边开始并向肺中心进展的独特模式。 最近的研究了解了该疾病从外周到中心进展的机制。 表明肺外周的实质扩张（应变）水平较高，有助于放大和 使初始肺损伤后纤维化的进展永久化。 肺纤维化的进展一直具有挑战性且成本高昂，因为（1）相关数据 由于疾病进展时间较长，肺病理学和肺力学都很难获得 人类；（2）最常用的博来霉素诱导的纤维化小鼠模型可自发消退并 因此无法完全反映人类纤维化，并且（3）当前的体外肺组织模型不能重现体内纤维化。 体内应变梯度和天然肺泡结构中存在的复杂生物力学。 该项目的目的是了解肺纤维化和机械拉伸之间的时空关系 并开发拉伸工程肺切片 (ELS) 模型来研究多尺度生物力学 差异拉伸引起的肺纤维化空间进展的机制主要假设是。 肺周边的高水平机械拉伸会放大受损肺中的促纤维化信号 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ELS 结构持久的人肺支架中的肺细胞利用 ELS 研究纤维化。 随着进展，研究人员计划采用多尺度仿生策略，将 ELS 与 梯度拉伸装置可以对肺周围存在的差异应变进行宏观建模 和肺中心，并且 ELS 中保留的结构允许对机械信号进行微观建模 目的包括表征单肺泡水平上存在的转导和细胞损伤。 人和大鼠纤维化肺中肺纤维化和机械拉伸的时空演变 样本，开发差异拉伸 ELS 模型来测试实际应变梯度如何影响空间 上皮损伤后纤维化的进展，并了解纤维化的多尺度生物力学机制 拉伸诱导纤维化的发生和进展。机械拉伸和计算的结合。 使用肺切片模型进行建模将大大提高这种未充分利用的肺模型的实用性 疾病研究，从而极大地促进了肺纤维化的研究工作，提高了 对过去未得到充分研究的主要疾病机制的了解。