Preserving Epithelial Barrier Integrity in Ventilator-Induced Lung Injury

在呼吸机引起的肺损伤中保持上皮屏障的完整性

基本信息

批准号：
10186793
负责人：
Jason HT Bates
金额：
$ 63.3万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10186793
关键词：
Acceleration Acute Lung Injury Address Adult Respiratory Distress Syndrome Alveolar Alveolus Anatomy Animal Model Appearance Biological Markers Biological Models Biophysical Process Bioreactors Blood gas Bronchoalveolar Lavage Fluid Cell Death Computer Models Critical Care Data Development Diagnosis Drug Targeting Elements Endothelium Epithelial Epithelial Cells Event Family suidae Goals Histology Human Impairment In Vitro Individual Injury Intensive Care Units Interruption Intervention Lead Life Liquid substance Lung Lung Compliance Mechanical Stress Mechanical ventilation Mechanics Medicine Modeling Mus Pathogenesis Patients Perforation Periodicity Pharmacologic Substance Plasma Primary Prevention Process Proteins Recording of previous events Recovery Regimen Research Risk Stress Stretching Structure of parenchyma of lung Study models Supportive care Surface Tension Techniques Testing Tight Junctions Time Tissues Tube Ventilator-induced lung injury Volutrauma airway epithelium atelectrauma clinically relevant design event cycle improved in vivo lung injury monolayer mortality multi-scale modeling patient population personalized approach predictive modeling preservation prevent pulmonary function rate of change recruit repaired surfactant surfactant function tissue stress tool ventilation

项目摘要

PROJECT SUMMARY The distressingly high mortality from acute respiratory distress syndrome (ARDS) represents a dramatic loss of quality human life-years. No medicines have yet been developed that treat ARDS, so management remains purely supportive as patients are nursed through their illness in a critical care setting. A key component of this management involves mechanical ventilation. Unfortunately, the stresses and strains of mechanical ventilation can further damage already injured lung tissues, causing lung compliance to decrease and the stresses and strains of mechanical ventilation to increase commensurately. This, in turn, worsens tissue damage in a vicious cycle that is often ultimately fatal. Accordingly, the central premise of this proposal is that managing ARDS requires, above all else, the minimization of VILI. Our prior studies lead to the over-arching hypothesis that the development of ARDS occurs only once repetitive recruitment and derecruitment (RecDer) of lung units initiates an epithelial leak that allows fluid and proteins to begin to accumulate in the airspaces. The consequences of allowing this process to start are dire; surfactant function becomes impaired, surface tension and tissue stresses increase, and the leak worsens in a vicious cycle that accelerates indefinitely. Once underway, this process is difficult to reverse and is exacerbated by over-distension (OD) of the lung tissues, making its avoidance paramount for patients at risk of developing ARDS. Our goal is to comprehensively test this hypothesis both in vitro and in vivo in a range of three relevant model systems: 1) using biofluid mechanics studies we will investigate fundamental interactions that may lead to RecDer, and at the cellular level in vitro we will determine how both OD of lung tissue and repetitive RecDer of lung airspaces act individually and synergistically to damage the airway epithelium in epithelial cell monolayers grown on the inside of compliant tubes subjected to stretch and/or liquid bubble passage, respectively, 2) at the whole lung level in vivo we will determine how over-distension and RecDer lead to leak of proteinaceous fluid into the lung airspaces and cause derangements in lung mechanics and 3) we will determine how VILI can be minimized in a clinically relevant porcine surfactant deactivation model of heterogeneous ARDS subjected to a variety of modes of mechanical ventilation that apply differing relative degrees of tissue over-distention and RecDer. The data collected in Aims 1 and 2 will inform the development of a computational model that predicts how VILI develops over time as a result of the epithelial damage caused by RecDer and the exacerbating influences of overdistension. The model will be tested under clinically relevant conditions in Aim 3. These studies will establish the pathophysiologic understanding upon which personalized approaches to mechanical ventilation that minimize VILI can be developed for individual ARDS patients.

项目摘要急性呼吸窘迫综合征（ARDS）的令人痛苦的高死亡率代表了巨大的丧失优质的人类生活年。尚未开发出治疗ARDS的药物，因此管理仍然存在在重症监护环境中，由于患者的疾病而受到护理，纯粹的支持。一个关键组成部分管理涉及机械通气。不幸的是，机械通气的应力和应变可能会进一步损害已经受伤的肺组织，从而导致肺依从性减少和压力和压力机械通气的菌株相应增加。反过来，这会使组织损伤恶化循环通常是致命的。因此，该提议的主要前提是管理ARDS 最重要的是，Vili的最小化。我们先前的研究导致了一个超大的假设 ARDS的发展仅发生一次重复招募和肺单位的授予（RECDER）引发上皮泄漏，该泄漏使流体和蛋白质开始在空域中积聚。这允许这个过程开始的后果是可怕的。表面活性剂功能受损，表面张力组织应力增加，泄漏在恶性循环中加剧，无限期加速。一次正在进行中，这个过程很难逆转，并且因肺组织的过度距离（OD）而加剧对于有患ARDS的风险的患者，使其避免至高无上。我们的目标是全面测试该假设在体外和体内均在三个相关模型系统中：1）使用生物流体力学研究我们将研究可能导致收益的基本相互作用，并在细胞水平上体外我们将确定肺组织的OD和肺空间的重复性伴侣如何单独起作用协同损害在符合条件的内部生长的上皮细胞单层中的气道上皮管道分别受到拉伸和/或液体气泡通道的约束，2）在整个肺水中，我们将确定过度距离和回收器如何导致蛋白质流体泄漏到肺空间和原因是肺力学中的危险和3）我们将确定如何在临床上最小化VILI 相关的猪表面活性剂失活模型的异质ARDS受到多种模式机械通气应用不同的组织相对程度的过度距离和收获。数据在目标1和2中收集的将告知一个计算模型的开发，该模型可以预测Vili 随着时间的流逝，由于收获者造成的上皮损害和加剧的影响而发展过度差异。该模型将在AIM 3中的临床相关条件下进行测试。这些研究将建立对机械通气的个性化方法的病理生理理解可以为个别ARDS患者开发最小化VILI。