Biophysical Mechanisms of Hyperoxia-Induced Lung Injury

高氧引起的肺损伤的生物物理机制

• 批准号: 10614659
• 负责人: CHRISTOPHER M WATERS
• 金额: $ 52.23万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614659
• 关键词: Acceleration; Actins; Acute Lung Injury; Acute Respiratory Distress Syndrome; Alveolar; Animal Model; Antioxidants; Apoptosis; Atomic Force Microscopy; Bacterial Pneumonia; Basement membrane; Biological; Biophysical Process; Biophysics; Bone Marrow; Cell Adhesion; Cell Death; Cell membrane; Cells; Clinical; Cultured Cells; Cytoskeleton; Disease; Elasticity; Elements; Endothelial Cells; Endothelium; Epithelial Cells; Epithelium; Exposure to; F-Actin; Focal Adhesions; Gelsolin; Guanosine Triphosphate Phosphohydrolases; Human; Hyperoxia; Incidence; Inflammasome; Inflammation; Inflammatory; Influenza; Injury; Intensive Care Units; Investigation; Knock-out; Light; Lung; MYLK gene; Macrophage; Masks; Measures; Mechanical ventilation; Mechanics; Mediating; Microtubules; Modeling; Modulus; Mus; Myosin ATPase; Myosin Light Chains; Necrosis; Oxygen; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Predisposition; Preparation; Process; Proteins; Resistance; Rho-associated kinase; Rupture; Severities; Signal Pathway; Signal Transduction; Slice; Stretching; Structure; Structure of parenchyma of lung; Testing; Therapeutic Intervention; Tidal Volume; Ventilator-induced lung injury; Work; alveolar epithelium; biophysical properties; cell injury; ezrin; hyperoxia induced lung injury; improved; injured; insight; keratinocyte growth factor; lung injury; mechanical pressure; mechanical properties; mechanical signal; mechanotransduction; moesin; mortality; mouse model; myosin phosphatase; prevent; radixin protein; response; supplemental oxygen; targeted treatment

Acute lung injury and its more severe form, acute respiratory distress syndrome (ARDS), are devastating illnesses with high rates of incidence and mortality. Patients with acute lung injury are typically provided supplemental oxygen using positive pressure mechanical ventilation, but this can lead to additional injury, termed ventilator- induced lung injury (VILI). The long term objective of this proposal is to improve understanding of the mechanisms by which the combination of exposure to high levels of oxygen (hyperoxia) and overdistention (or stretch) of lung cells contributes to ventilator-induced lung injury. The central hypothesis of this application is that hyperoxia induces structural changes in alveolar epithelial and endothelial cells, as well as macrophages, that alter their mechanical properties making them more susceptible to injury caused by mechanical stretch. Mechanisms of the initiation of cell injury will be investigated using primary cultures of mouse alveolar type II (AT2) epithelial cells, primary human lung endothelial cells, mouse alveolar and bone marrow-derived macrophages, cultures of mouse lung slices, and a mouse model of combined hyperoxia and VILI. In Aim 1 we will test the hypothesis that exposure of cells or lung slices causes changes in cell structural elements that increase the elastic modulus of the cells through activation of RhoA. We will measure the Young’s modulus, an indication of an object’s ability to deform, using atomic force microscopy in the indentation mode, and we will determine how hyperoxia changes cytoskeletal structures including f-actin, microtubules, and focal adhesions. In Aim 2 we will investigate how hyperoxia increases stretch-induced cell detachment and injury. In Aim 3 we will test the hypothesis that RhoA-mediated changes in structure and mechanical properties increases lung injury in mice in a combined model of hyperoxia and VILI. The proposed studies will investigate the biophysical mechanisms that contribute to lung injury during mechanical ventilation and provide new insights into mechanotransduction, the process of converting mechanical signals to biological signals.

急性肺损伤及其更严重的形式，急性呼吸窘迫综合征 急性呼吸窘迫综合征（ARDS）是具有高发病率和死亡率的毁灭性疾病。患者 急性肺损伤患者通常使用正压通气提供补充氧气， 压力机械通气，但这可能导致额外的伤害，称为呼吸机- 肺损伤（VILI）。这项建议的长远目标是改善 了解接触高浓度汞的组合 氧（高氧）和过度膨胀（或拉伸）的肺细胞有助于 呼吸机引起的肺损伤本申请的中心假设是， 高氧还可引起肺泡上皮细胞和内皮细胞的结构变化， 如巨噬细胞，改变其机械特性，使其更容易受到 机械拉伸造成的损伤。细胞损伤的起始机制将是 使用小鼠肺泡II型（AT 2）上皮细胞的原代培养物进行研究， 小鼠肺泡和骨髓来源的原代人肺内皮细胞 巨噬细胞，小鼠肺切片的培养物，和小鼠模型的组合， 高氧和VILI。在目标1中，我们将检验细胞或肺暴露的假设， 切片引起细胞结构元件的变化， 通过激活RhoA来激活细胞。我们将测量杨氏模量， 使用原子力显微镜来指示物体的变形能力 压痕模式，我们将确定如何高氧改变细胞骨架结构 包括F-肌动蛋白、微管和粘着斑。在目标2中，我们将研究如何 高氧增加牵张诱导的细胞脱离和损伤。在目标3中，我们将测试 RhoA介导的结构和机械性能变化的假设 在高氧和VILI联合模型中增加小鼠肺损伤。拟议 研究将调查生物物理机制，有助于肺损伤， 机械通气，并提供新的见解mechanotransduction，过程 将机械信号转化为生物信号。