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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：
10374099
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10374099
关键词：
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 Disease Elements Endothelial Cells Endothelium Epithelial Epithelial Cells Exposure to F-Actin Focal Adhesions Gelsolin Guanosine Triphosphate Phosphohydrolases Human Hyperoxia Incidence Inflammasome Inflammation Inflammatory Influenza Injury Intensive Care Units Investigation Knock-out Lead Light Lung MYLK gene Masks Measures Mechanical ventilation Mechanics Mediating Microtubules Modeling Modulus Mus Myosin ATPase Myosin Light Chains Necrosis Oxygen Pathway interactions Patients 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 bone alveolar epithelium biophysical properties cell injury ezrin hyperoxia induced lung injury improved injured insight keratinocyte growth factor lung injury macrophage 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