VENTILATOR-ASSOCIATED ALVEOLAR EPITHELIAL INJURY

呼吸机相关的肺泡上皮损伤

• 批准号: 6764069
• 负责人: JAMES A FRANK
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6764069
• 关键词: alveolar macrophages; biological fluid transport; disease /disorder model; integrins; interleukin 1; laboratory mouse; laboratory rat; lung injury; pulmonary edema; respirators; respiratory airway volume; respiratory epithelium; therapy adverse effect; transforming growth factors

DESCRIPTION: (provided by applicant): Recent clinical studies have found that low tidal volume ventilation dramatically decreases mortality from the acute respiratory distress syndrome; however, the mechanism of the protective effect is not completely understood. The overall hypothesis of the proposed studies is that high tidal volumes injure the alveolar epithelium by inducing stretch-responsive changes in lung macrophages and alveolar epithelial cells that promote inflammation and impair alveolar epithelial sodium and fluid transport. Preservation of alveolar fluid transport is both a marker of epithelial injury and a mechanism by which ventilator-associated lung injury is attenuated because 1) flooding of the alveolar airspace contributes to the overdistention and injury of other, air-filled alveoli, and 2) airspace edema inactivates surfactant promoting atelectasis and lung volume loss. Aim 1 will determine whether mechanical ventilation activates alveolar and interstitial macropha-es in normal lungs and if macrophages are important in the amplification of alveolar epithelial and lung endothelial injury in a clinically relevant rat model of ventilator-associated lung injury. Preliminary data indicate that higher tidal volumes within a clinically- applicable range induce a greater increase in plasma IL-113 in this model. Alveolar epithelial injury as measured by biochemical markers, functional markers, and histology is incrementally reduced as tidal volume is decreased from 12 ml/kg to 3 ml/kg, at similar levels of end-expiratory pressure. Aim 2 will determine whether products of macrophage activation inhibit alveolar epithelial fluid transport and whether impaired alveolar epithelial sodium and fluid transport is important in the pathogenesis of VALI in murine models. Preliminary data show that alveolar epithelial sodium and fluid transport decrease as tidal volume is increased. Aim 3 will determine whether the activation of macrophage-derived TGF-beta2 by the epithelial integrin alpha1beta2 is important to alveolar epithelial and lung endothelial injury in ventilator-associated lung injury. Preliminary data show that the absence of beta2 integrin confers protection from acute lung injury. The environment at the Cardiovascular Research Institute, including mentoring, laboratory facilities, scientific conferences, and formal coursework will provide me with an ideal setting to further advance my skills as an investigator. This research and comprehensive career development plan will prepare me to become an independent investigator in the mechanisms of alveolar epithelial injury and ventilator-associated lung injury.

描述：（申请人提供）： 最近的临床研究发现，潮汐量低。 急性呼吸窘迫综合征的死亡率大大降低； 但是，保护效应的机制并非完全 理解。 提出的研究的总体假设是高潮 通过诱导拉伸响应变化来损害肺泡上皮 在肺巨噬细胞和肺泡上皮细胞中 炎症和损害肺泡上皮钠和液体转运。 牙槽液传输的保存既是上皮损伤的标志 以及一种使呼吸机相关的肺损伤的机制 因为1）肺泡空域的洪水有助于过度存在 以及其他充气肺泡的伤害，以及2）空体水肿灭活 表面活性剂促进肺不症和肺部体积损失。 AIM 1将确定机械通气是否激活肺泡和 正常肺中的间质巨噬细胞，如果巨噬细胞在 肺泡上皮和肺内皮损伤的扩增 临床相关的呼吸机相关肺损伤的大鼠模型。 初步数据表明，在临床上 - 在此模型中，适用范围会引起血浆IL-113的更大增加。 通过生化标记测量的肺泡上皮损伤，功能性 标记物，随着潮汐体积的减少，组织学逐渐减少 从12 mL/kg到3 mL/kg，在验证压力的相似水平下。 AIM 2将确定巨噬细胞激活的产物是否抑制 肺泡上皮流体转运以及肺泡上皮是否受损 钠和流体转运在瓦利的发病机理中很重要 鼠模型。 初步数据表明肺泡上皮钠和 随着潮汐体积的增加，流体转运减小。 AIM 3将确定 上皮的激活是否激活巨噬细胞的TGF-BETA2 整联蛋白alpha1beta2对肺泡上皮和肺内皮很重要 呼吸机相关的肺损伤受伤。 初步数据表明 缺乏β2整联蛋白会赋予急性肺损伤的保护。 心血管研究所的环境，包括指导， 实验室设施，科学会议和正式课程将 为我提供理想的环境，以进一步提高我的技能 研究者。 这项研究和全面的职业发展计划将 我准备成为肺泡机制的独立研究者 上皮损伤和呼吸机相关的肺损伤。