Probing immunovascular mechanobiology in pneumonia-associated acute lung injury at the single capillary level

在单毛细血管水平探讨肺炎相关急性肺损伤的免疫血管力学生物学

• 批准号: 10679944
• 负责人: Linzheng Shi
• 金额: $ 5.27万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679944
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Affect; Air; Alveolar; Alveolus; Biology; Biophysical Process; Blood Vessels; Blood capillaries; Boston; Cells; Circulation; Communication; Coupled; Data; Diffusion; Edema; Endothelium; Erythrocytes; Event; Experimental Designs; Fellowship; Functional disorder; Gases; Goals; Heterogeneity; Histologic; Hypoxia; Image; Immune; Immunity; Immunobiology; Immunology; Impairment; Infiltration; Inflammation; Inflammatory; Injury; Intervention; Knowledge; Label; Life; Link; Liquid substance; Lung; Macrophage; Magnetic Resonance Imaging; Mechanical ventilation; Mechanics; Mentorship; Microcirculation; Microscopy; Molecular Profiling; Mus; Myeloid Cells; Optics; Organ; Oxygen; Pathogenesis; Perfusion; Phagocytosis; Phenotype; Physicians; Physics; Physiology; Pneumonia; Prone Position; Pulmonary Ventilation; Reporter; Research; Resolution; Respiratory Failure; Role; Scientist; Streptococcus pneumoniae; Structure; Surface; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Universities; Visualization; Work; X-Ray Computed Tomography; alveolar epithelium; career; cell motility; cell type; clinical practice; epithelial injury; hemodynamics; imaging modality; immune function; improved; in vivo; interdisciplinary approach; lung imaging; lung injury; lung preservation; migration; mortality; mouse model; new technology; novel; novel therapeutics; oxygen transport; pathogen; physical science; pre-doctoral; preservation; pressure; pulmonary function; real-time images; recruit; respiratory; response; rib bone structure; temporal measurement; therapeutically effective; trafficking; transcriptomics; ventilation; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Affect; Air; Alveolar; Alveolus; Biology; Biophysical Process; Blood Vessels; Blood capillaries; Boston; Cells; Circulation; Communication; Coupled; Data; Diffusion; Edema; Endothelium; Erythrocytes; Event; Experimental Designs; Fellowship; Functional disorder; Gases; Goals; Heterogeneity; Histologic; Hypoxia; Image; Immune; Immunity; Immunobiology; Immunology; Impairment; Infiltration; Inflammation; Inflammatory; Injury; Intervention; Knowledge; Label; Life; Link; Liquid substance; Lung; Macrophage; Magnetic Resonance Imaging; Mechanical ventilation; Mechanics; Mentorship; Microcirculation; Microscopy; Molecular Profiling; Mus; Myeloid Cells; Optics; Organ; Oxygen; Pathogenesis; Perfusion; Phagocytosis; Phenotype; Physicians; Physics; Physiology; Pneumonia; Prone Position; Pulmonary Ventilation; Reporter; Research; Resolution; Respiratory Failure; Role; Scientist; Streptococcus pneumoniae; Structure; Surface; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Universities; Visualization; Work; X-Ray Computed Tomography; alveolar epithelium; career; cell motility; cell type; clinical practice; epithelial injury; hemodynamics; imaging modality; immune function; improved; in vivo; interdisciplinary approach; lung imaging; lung injury; lung preservation; migration; mortality; mouse model; new technology; novel; novel therapeutics; oxygen transport; pathogen; physical science; pre-doctoral; preservation; pressure; pulmonary function; real-time images; recruit; respiratory; response; rib bone structure; temporal measurement; therapeutically effective; trafficking; transcriptomics; ventilation

PROJECT SUMMARY/ABSTRACT Acute respiratory distress syndrome (ARDS) and its less severe form, acute lung injury (ALI), are devastating, life-threatening respiratory illnesses that can result from pneumonia. Injury to the alveolar epithelial-endothelial barrier in ARDS results in alveolar edema that mechanically impairs alveolar distensibility, hinders gas exchange, and promotes inflammation. Disruption of normal lung mechanics and biology demonstrate the need to study ARDS at the intersection of lung immunobiology and physical sciences. The importance of lung mechanobiology is reflected by current effective therapeutic interventions that target lung mechanics, such as protective mechanical ventilation and prone positioning. While ARDS edema is known to compromise alveolar mechanics, the downstream consequences on capillary mechanics, hemodynamics, and oxygen transport are not well known. As a result, it remains unknown how altered capillary function in ARDS affects the trafficking, sequestration, migration, and phagocytosis of key immune cell types, such as resident and recruited macrophages. Our understanding of ARDS microphysiology is limited by a technological gap to study lung respiratory-circulatory function at the cellular scale in real-time. Current imaging modalities such as MRI/CT and histological analyses lack the necessary spatial and temporal resolution to probe dynamic events such as vascular flow, cellular trafficking and migration, and gas exchange. To address these needs, we have developed a novel “LungEx” system that allows mechanistic probing of lung respiratory-circulatory function in real-time at the single capillary scale. LungEx is an ex vivo ventilated and perfused murine lung with preserved physics and biology near that of in vivo lungs, combined with a transparent “crystal” ribcage to allow high- resolution optical microscopy of capillary function in real-time. Combining LungEx with experimental murine models of ALI caused by pneumonia (PNA-ALI), we have preliminarily observed altered capillary function in edematous PNA-ALI regions. Here, utilizing LungEx, we will test the hypotheses that: altered alveolar mechanics in PNA-ALI impairs capillary mechanics, restricts RBC flow trafficking, and hence reduces oxygen transport on the capillary scale (Aim 1); and altered mechanics in PNA-ALI differentially impedes resident vs recruited macrophage function, promoting a mechanosensitive inflammatory profile (Aim 2). These studies will improve our understanding of the mechanobiology and mechanoimmunity underlying pneumonia-associated ARDS pathogenesis that begins on the single capillary level and how it affects key immunovascular components of the lung. As part of the pre-doctoral fellowship training towards a physician-scientist career, the proposed work will emphasize hypothesis-based experimental design, scientific communication and mentorship, integration of research with clinical practice, and will be carried out at Boston University.

项目摘要/摘要 急性呼吸窘迫综合征（ARDS）及其不太严重的急性肺损伤（ALI）是毁灭性的， 肺炎可能导致的威胁生命的呼吸道疾病。肺泡上皮内端损伤 ARDS中的障碍会导致肺泡水肿，从而机械损害肺泡的扩张性，阻碍气体 交换并促进感染。正常肺部力学和生物学的破坏证明了需求 在肺部免疫生物学和物理科学的交集中研究ARDS。肺的重要性 机械生物学反映了针对肺部力学的当前有效治疗干预措施，例如 保护性机械通气和俯卧位定位。虽然已知ARDS水肿会损害肺泡 力学，下游对毛细管力学，血液动力学和氧运输的后果是 不知道。结果，ARDS中毛细血管功能的变化如何影响贩运， 关键免疫物类型的隔离，迁移和吞噬作用，例如居民和招募 巨噬细胞。我们对ARDS微生物生理学的理解受到研究肺的技术差距的限制 实时在细胞尺度上的呼吸循环功能。当前的成像方式，例如MRI/CT 组织学分析缺乏必要的空间和临时分辨率来探测动态事件，例如 血管流，细胞运输和迁移以及气体交换。为了满足这些需求，我们有 开发了一种新型的“弓形”系统，该系统允许在机械上探测肺呼吸道循环功能 实时在单个毛细管尺度上进行实时。 Lungex是一个未经液体的体内通风和灌注的鼠肺 物理和生物学附近的体内肺，结合透明的“晶体”柱 毛细管功能的分辨率光学显微镜实时。将弓箭与实验鼠结合 由肺炎引起的ALI模型（PNA-ALI），我们在初步观察到的毛细血管功能改变了 水肿PNA-ALI区域。在这里，使用弓箭，我们将测试以下假设：改变肺泡 PNA-ALI中的力学会损害毛细管力学，限制RBC流量运输，因此减少了氧气 在毛细管尺度上运输（AIM 1）； PNA-ALI中的力学改变对居民VS的影响不同 募集的巨噬细胞功能，促进机械敏感的炎症谱（AIM 2）。这些研究会 提高我们对与肺炎相关的基本机械性生物学和机械免疫的理解 ARDS发病机理始于单个毛细管水平及其如何影响关键免疫血管 肺部成分。作为对身体科学家职业的博士前奖学金培训的一部分， 拟议的工作将强调基于假设的实验设计，科学交流和 属性，研究与临床实践的整合，并将在波士顿大学进行。