Stretch and Hyperoxia in Ventilator-induced Lung Injury

呼吸机引起的肺损伤中的牵张和高氧

基本信息

批准号：
7842076
负责人：
SCOTT E SINCLAIR
金额：
$ 21.51万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7842076
关键词：
Acute Acute Lung Injury Address Adult Respiratory Distress Syndrome Alveolar Animal Model Antioxidants Apoptosis Apoptotic Blood Blood capillaries Cell Death Cells Clinical Trials Data Development Environmental air flow Epithelial Epithelial Cells Exposure to Functional disorder Gases Genes Human Hyperoxia Hypoxemia In Vitro Infection Inflammation Mediators Injury Intervention Link Liquid substance Lung MAP Kinase Gene MAP3K5 gene MAPK14 gene Mechanical ventilation Mechanics Mediating Oxidases Oxygen Pathogenesis Pathway interactions Patients Permeability Phosphotransferases Prevention Production Proteins Rattus Reactive Oxygen Species Research Personnel Respiratory Failure Signal Transduction Small Interfering RNA Stimulus Stretching System Tidal Volume Tissues Type II Epithelial Receptor Cell Ventilator-induced lung injury Work capillary cell type clinical application improved in vivo in vivo Model inhibitor/antagonist interstitial lung injury monolayer mortality mouse model prevent programs response theories therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Both mechanical ventilation and hyperoxia, although necessary supportive interventions, have been independently implicated in the genesis of lung injury. Although patients with hypoxemic respiratory failure are routinely exposed to both of these interventions, little is known about their potential adverse interaction. We hypothesize that cyclic stretch of alveolar epithelial cells caused by mechanical ventilation, in the presence of moderate hyperoxia, causes an increase in production of reactive oxygen species (ROS) that is greater than that produced by either stimulus alone. These excess ROS, through altered oxidative signaling, result in increased apoptotic cell death of alveolar epithelial cells. The resulting cell loss leads to the breakdown of alveolar-epithelial barrier integrity causing the lungs to become more permeable to fluid, cells, and inflammatory mediators. This influx of fluid and cells causes adverse derangement in lung mechanics and gas exchange, and the accelerated development of lung injury. In the proposed studies, we will use an in vivo model of lung injury caused by the combined effect of large tidal volume mechanical ventilation and moderate hyperoxia, an in vitro system that allows cyclic mechanical stretch of isolated alveolar epithelial cell monolayers in hyperoxic conditions as well as isolation of alveolar type II epithelial cells from rats after exposure to mechanical ventilation and hyperoxia. We will use these systems to accomplish the following specific aims: Specific Aim 1: To demonstrate that the combination of mechanical stretch and moderate hyperoxia leads to early loss of alveolar-capillary barrier integrity and accelerated development of lung injury. Specific Aim 2: To determine the mechanisms by which ROS are produced during mechanical stretch and hyperoxia in cultured alveolar epithelial cells. Specific Aim 3: To demonstrate that COMBINED mechanical stretch and moderate hyperoxia increases alveolar type II epithelial cell apoptosis via activation of apoptosis signal-regulating kinase-1 (ASK-1) and to determine the effect of ASK-1 mediated apoptosis on alveolar epithelial barrier integrity. Because ALI patients supported with mechanical ventilation receive varied levels of supplemental oxygen, the proposed work could have significant clinical applicability, including the identification of potential therapeutic targets for the prevention and/or treatment of acute lung injury.

描述（由申请人提供）：机械通气和高氧虽然是必要的支持性干预措施，但都独立地涉及肺损伤的发生。尽管低氧血症性呼吸衰竭患者经常接受这两种干预措施，但对其潜在的不良相互作用知之甚少。我们假设，在中度高氧存在的情况下，由机械通气引起的肺泡上皮细胞的周期性拉伸会导致活性氧（ROS）产生的增加，其产生的量比单独刺激产生的要多。这些过量的 ROS 通过改变氧化信号传导，导致肺泡上皮细胞凋亡增加。由此产生的细胞损失导致肺泡上皮屏障完整性破坏，导致肺部变得更容易渗透液体、细胞和炎症介质。液体和细胞的流入导致肺力学和气体交换的不利紊乱，并加速肺损伤的发展。在拟议的研究中，我们将使用由大潮气量机械通气和适度高氧联合作用引起的肺损伤体内模型，这是一种体外系统，允许在高氧条件下分离的肺泡上皮细胞单层进行循环机械拉伸暴露于机械通气和高氧后，从大鼠体内分离出肺泡 II 型上皮细胞。我们将使用这些系统来实现以下具体目标：具体目标 1：证明机械拉伸和适度高氧的结合会导致肺泡毛细血管屏障完整性的早期丧失并加速肺损伤的发展。具体目标 2：确定培养的肺泡上皮细胞在机械拉伸和高氧过程中产生 ROS 的机制。具体目标 3：证明机械拉伸和适度高氧相结合可通过激活凋亡信号调节激酶 1 (ASK-1) 增加肺泡 II 型上皮细胞凋亡，并确定 ASK-1 介导的细胞凋亡对肺泡上皮屏障的影响正直。由于接受机械通气支持的 ALI 患者接受不同水平的补充氧气，因此拟议的工作可能具有重要的临床适用性，包括确定预防和/或治疗急性肺损伤的潜在治疗靶点。