Biophysical Mechanisms of Hyperoxia-Induced Lung Injury

高氧引起的肺损伤的生物物理机制

基本信息

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
项目类别：
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

项目摘要

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) 是毁灭性的痛苦，发病率和死亡率很高。对于急性肺损伤，通常使用正压供氧压力机械通气，但这可能会导致额外的伤害，称为呼吸机- 该提案的长期目标是改善诱发性肺损伤（VILI）。了解高水平暴露组合的机制氧气不足（高氧）和肺细胞过度膨胀（或拉伸）会导致该应用的中心假设是呼吸机引起的肺损伤。高氧还会引起肺泡上皮细胞和内皮细胞的结构变化作为巨噬细胞，改变它们的机械特性，使它们更容易受到影响机械拉伸引起的损伤是细胞损伤的起始机制。使用小鼠 II 型肺泡 (AT2) 上皮细胞的原代培养物进行研究，原代人肺内皮细胞、小鼠肺泡和骨髓来源巨噬细胞、小鼠肺切片培养物以及组合的小鼠模型高氧和 VILI 在目标 1 中，我们将检验细胞或肺暴露的假设。切片会导致细胞结构元素发生变化，从而增加弹性模量我们将测量杨氏模量，即 RhoA 的激活。使用原子力显微镜来指示物体变形的能力压痕模式，我们将确定高氧如何改变细胞骨架结构包括 f-肌动蛋白、微管和粘着斑，在目标 2 中我们将研究如何进行。高氧会增加拉伸引起的细胞脱离和损伤。在目标 3 中，我们将进行测试。 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的肺损伤。研究将调查导致肺损伤的生物物理机制机械通气并为机械传导过程提供新的见解将机械信号转换为生物信号。