VENTILATOR-ASSOCIATED ALVEOLAR EPITHELIAL INJURY

描述：（申请人提供）： 最近的临床研究发现，低潮气量通气 显著降低急性呼吸窘迫综合征的死亡率; 然而，其保护作用的机制并不完全 明白 拟议研究的总体假设是， 体积通过诱导牵张反应性变化而损伤肺泡上皮 在肺巨噬细胞和肺泡上皮细胞中， 炎症和受损肺泡上皮钠和液体转运。 肺泡液体运输的保存既是上皮损伤的标志 以及减轻呼吸机相关肺损伤的机制 因为1）肺泡空气空间的泛滥导致过度膨胀 以及其他充气肺泡的损伤，以及2）空域水肿失活 表面活性剂促进肺不张和肺容量损失。 目的1将确定机械通气是否激活肺泡和 间质巨噬细胞在正常肺中是否重要， 肺泡上皮细胞和肺内皮细胞损伤放大 呼吸机相关肺损伤的临床相关大鼠模型。 初步数据表明，较高的潮气量在临床- 在该模型中，可应用的范围诱导血浆IL-113的更大增加。 通过生化标记物测量的肺泡上皮损伤，功能 标记物，并且组织学随着潮气量减少而逐渐减少 从12 ml/kg至3 ml/kg，在相似的呼气末压水平下。 目的2将确定巨噬细胞活化的产物是否抑制 肺泡上皮液体转运和肺泡上皮细胞是否受损 钠和液体转运在VALI的发病机制中是重要的， 鼠模型。 初步数据显示，肺泡上皮钠和 液体输送随着潮气量的增加而减少。目标3将决定 上皮细胞对巨噬细胞源性TGF-β 2的激活是否 整合素α 1 β 2对肺泡上皮和肺内皮细胞 呼吸机相关性肺损伤中的损伤。 初步数据显示， β 2整联蛋白的缺乏提供了对急性肺损伤的保护。 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 为我提供了一个理想的环境，以进一步提高我的技能， 调查员 这项研究和全面的职业发展计划将 准备我成为一个独立的调查机构在肺泡 上皮损伤和呼吸机相关的肺损伤。

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.