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 (ARDS)是一种发病率和死亡率都很高的破坏性疾病。病人 对于急性肺损伤，通常使用阳离子提供补充氧气 加压机械通风，但这可能会导致额外的伤害，称为呼吸机- 诱导肺损伤(VILI)。这项提议的长期目标是改善 对高水平暴露组合的机制的理解 氧气(高氧)和肺细胞过度膨胀(或拉伸)导致 呼吸机所致肺损伤。这个应用程序的中心假设是 高氧还可引起肺泡上皮细胞和内皮细胞的结构改变 作为巨噬细胞，这改变了它们的机械性能，使它们更容易受到 到机械拉伸造成的损伤。启动细胞损伤的机制将是 使用小鼠肺泡II型(AT2)上皮细胞的原代培养进行研究， 原代人肺内皮细胞、小鼠肺泡和骨髓来源 巨噬细胞，小鼠肺切片培养，以及联合的小鼠模型 高氧血症和VILI。在目标1中，我们将测试细胞或肺暴露的假设 切片会导致细胞结构元素发生变化，从而增加细胞的弹性系数 通过激活RhoA激活细胞。我们将测量杨氏模数， 物体变形能力的指示，使用原子力显微镜在 压痕模式，我们将确定高氧如何改变细胞骨架结构 包括f-肌动蛋白、微管和灶性粘连。在目标2中，我们将研究如何 高氧会增加牵张引起的细胞脱离和损伤。在目标3中，我们将测试 RhoA介导的结构和力学性能变化假说 在高氧和VILI联合模型中增加小鼠的肺损伤。建议数 研究将探讨导致肺损伤的生物物理机制 并提供了对机械转导的新见解，该过程 把机械信号转换成生物信号。