VENTILATOR-ASSOCIATED ALVEOLAR EPITHELIAL INJURY

描述：(申请人提供)： 最近的临床研究发现，低潮气量通气机 显著降低急性呼吸窘迫综合征的死亡率； 然而，其保护作用的机制还不完全清楚。 明白了。拟议研究的总体假设是涨潮 容量通过诱导拉伸反应改变损伤肺泡上皮 在肺巨噬细胞和肺泡上皮细胞中促进 炎症和损害肺泡上皮钠和液体的运输。 肺泡液运输的保存既是上皮损伤的标志 以及减轻呼吸机相关性肺损伤的机制 因为1)肺泡空隙的泛滥导致了过度扩张。 和其他充满空气的肺泡的损伤，以及2)空隙水肿失活。 肺表面活性物质促进肺不张和肺容量减少。 目标1将确定机械通气是否激活肺泡和 正常肺的间质巨噬细胞以及巨噬细胞在 肺泡上皮细胞和肺内皮细胞损伤的放大 临床相关的呼吸机相关性肺损伤大鼠模型。 初步数据显示，临床上较高潮气量- 在此模型中，适用范围可诱导血浆IL-113的较大幅度升高。 用生化标记物测定功能性肺泡上皮损伤 随着潮气量的减少，标记物和组织学逐渐减少 12毫升/公斤至3毫升/公斤，呼气末压力相近。 AIM 2将确定巨噬细胞激活产物是否抑制 肺泡上皮液转运与肺泡上皮损伤 钠和液体转运在VALI的发病机制中起重要作用 小鼠模型。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 上皮细胞是否激活巨噬细胞来源的转化生长因子-β2 整合素α1β2对肺泡上皮和肺内皮细胞的重要作用 呼吸机相关性肺损伤中的损伤初步数据显示， 缺乏β2整合素对急性肺损伤具有保护作用。 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，以进一步提高我作为 调查员。这项研究和全面的职业发展计划将 让我做好准备，成为一名肺泡机制的独立研究员 上皮损伤和呼吸机相关性肺损伤。

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.