Stretch and Hyperoxia in Ventilator-induced Lung Injury

呼吸机引起的肺损伤中的牵张和高氧

• 批准号: 7418233
• 负责人: SCOTT E SINCLAIR
• 金额: $ 31.9万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-05 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418233
• 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; Condition; Data; Development; Environmental air flow; Epithelial; Epithelial Cells; Exposure to; Functional disorder; Gases; Genes; Human; Hyperoxia; Hypoxemia; In Vitro; Infection; Inflammatory; Injury; Intervention; Link; Liquid substance; Lung; MAP Kinase Gene; MAP3K5 gene; MAPK14 gene; Mechanical ventilation; Mechanics; Mediating; Mediator of activation protein; NAD(P)H oxidase; Newborn Respiratory Distress Syndrome; 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

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，虽然必要的支持性干预，已独立地涉及肺损伤的发生。尽管低氧性呼吸衰竭患者常规暴露于这两种干预措施，但对其潜在的不良相互作用知之甚少。我们假设，在中度高氧存在下，机械通气引起的肺泡上皮细胞的周期性伸展导致活性氧（ROS）的产生增加，其大于单独刺激产生的活性氧。这些过量的ROS，通过改变氧化信号，导致肺泡上皮细胞的凋亡性细胞死亡增加。由此产生的细胞损失导致肺泡上皮屏障完整性的破坏，导致肺变得对液体、细胞和炎症介质更具渗透性。这种液体和细胞的流入导致肺力学和气体交换的不利紊乱，以及肺损伤的加速发展。在拟议的研究中，我们将使用一个体内模型的肺损伤所造成的大潮气量机械通气和中度高氧，体外系统，允许周期性机械拉伸分离肺泡上皮细胞单层在高氧条件下，以及隔离肺泡II型上皮细胞从大鼠暴露于机械通气和高氧的综合作用。我们将使用这些系统来实现以下具体目标：具体目标1：证明机械拉伸和中度高氧的组合导致肺泡毛细血管屏障完整性的早期丧失和肺损伤的加速发展。具体目标2：确定培养的肺泡上皮细胞在机械拉伸和高氧期间产生ROS的机制。具体目标3：证明机械牵拉和中度高氧联合作用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介导的凋亡对肺泡上皮屏障完整性的影响。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。