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: 7148293
• 负责人: SCOTT E SINCLAIR
• 金额: $ 32.85万
• 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/7148293
• 关键词: JUN kinase; NAD(P)H dehydrogenase; apoptosis; enzyme activity; enzyme induction /repression; free radical oxygen; histopathology; hyperoxia; laboratory mouse; laboratory rat; lung injury; mechanical stress; mitogen activated protein kinase; pathologic process; respirators; respiratory epithelium; small interfering RNA; therapy adverse effect; tissue /cell culture; vascular endothelium permeability

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）：尽管必要的支持干预措施，机械通气和高氧都与肺部损伤的起源有关。尽管通常会暴露于这两种干预措施的低氧呼吸衰竭患者，但对他们的潜在不良相互作用知之甚少。我们假设在存在中等高氧的情况下，由机械通气引起的肺泡上皮细胞的环状延伸会导致活性氧（ROS）的产生增加，而活性氧（ROS）的产生大于单独刺激产生的活性氧。这些多余的ROS通过改变的氧化信号传导导致肺泡上皮细胞的凋亡细胞死亡增加。所得的细胞损失导致肺泡上皮屏障完整性的崩溃，从而导致肺部对液体，细胞和炎症介质的渗透性。流体和细胞的这种涌入会导致肺力学和气体交换中的不良危险，以及肺损伤的加速发展。 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.我们将使用这些系统来实现以下特定目标：具体目的1：证明机械伸展和中等高氧的结合会导致肺泡毛细血管屏障完整性的早期丧失，并加速肺损伤的发育。特定目的2：确定在培养的肺泡上皮细胞中机械拉伸和高氧过程中产生ROS的机制。具体目的3：证明合并的机械拉伸和中等高氧通过激活凋亡信号调节激酶-1（ASK-1）来增加肺泡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。由于支持机械通气的ALI患者会接受各种水平的补充氧，因此拟议的工作可能具有明显的临床适用性，包括鉴定了预防和/或治疗急性肺损伤的潜在治疗靶标。