Preserving Epithelial Barrier Integrity in Ventilator-Induced Lung Injury

项目总结 急性呼吸窘迫综合征(ARDS)令人痛心的高死亡率意味着 高质量的人类寿命--年数。目前还没有开发出治疗ARDS的药物，因此管理仍在继续 完全是支持性的，因为病人在重症监护环境中得到了疾病的护理。这其中的一个关键组成部分 管理涉及机械通风。不幸的是，机械通风的压力和紧张 会进一步损害已经受损的肺组织，导致肺顺应性下降，应激和 机械通气量相应增加。这反过来又加剧了恶性血管内皮细胞的组织损伤。 这种循环往往最终是致命的。因此，这项提议的中心前提是管理ARDS 最重要的是，需要最小化Vili。我们之前的研究导致了一个总体假设，即 ARDS的发生只发生在肺单位的一次重复募集和去除(RecDer) 引发上皮渗漏，使液体和蛋白质开始在空气中积聚。这个 允许这一过程开始的后果是可怕的；表面活性物质的功能受到损害，表面张力 组织应力增加，泄漏在恶性循环中恶化，并无限期加速。一次 在进行中，这一过程很难逆转，并因肺组织过度膨胀(OD)而加剧， 对于有患ARDS风险的患者来说，避免它是最重要的。我们的目标是全面测试 这一假说在体外和体内都有三个相关的模型系统：1)使用生物流体力学 研究我们将研究可能导致RecDer的基本相互作用，并在体外细胞水平上 我们将确定肺组织的外径和重复的肺空间重复率如何单独和 协同损伤顺应性内层上皮细胞单层上皮细胞 分别承受拉伸和/或液体气泡通过的管，2)在活体的全肺水平上，我们将 确定过度扩张和重新扩张如何导致蛋白质液体泄漏到肺空隙和 导致肺力学紊乱和3)我们将确定如何在临床上最大限度地减少VILI 猪肺表面活性物质在多种模式下的异质性ARDS失活模型 应用不同相对程度的组织过度扩张和再膨胀的机械通气。数据 在目标1和目标2中收集的信息将用于开发预测VILI如何 随着时间的推移，由于RecDer引起的上皮损伤和 过度膨胀。该模型将在目标3中的临床相关条件下进行测试。这些研究将 建立对个性化机械通气方法的病理生理学理解 最大限度地减少VILI可以为个别ARDS患者开发。

PROJECT SUMMARY The distressingly high mortality from acute respiratory distress syndrome (ARDS) represents a dramatic loss of quality human life-years. No medicines have yet been developed that treat ARDS, so management remains purely supportive as patients are nursed through their illness in a critical care setting. A key component of this management involves mechanical ventilation. Unfortunately, the stresses and strains of mechanical ventilation can further damage already injured lung tissues, causing lung compliance to decrease and the stresses and strains of mechanical ventilation to increase commensurately. This, in turn, worsens tissue damage in a vicious cycle that is often ultimately fatal. Accordingly, the central premise of this proposal is that managing ARDS requires, above all else, the minimization of VILI. Our prior studies lead to the over-arching hypothesis that the development of ARDS occurs only once repetitive recruitment and derecruitment (RecDer) of lung units initiates an epithelial leak that allows fluid and proteins to begin to accumulate in the airspaces. The consequences of allowing this process to start are dire; surfactant function becomes impaired, surface tension and tissue stresses increase, and the leak worsens in a vicious cycle that accelerates indefinitely. Once underway, this process is difficult to reverse and is exacerbated by over-distension (OD) of the lung tissues, making its avoidance paramount for patients at risk of developing ARDS. Our goal is to comprehensively test this hypothesis both in vitro and in vivo in a range of three relevant model systems: 1) using biofluid mechanics studies we will investigate fundamental interactions that may lead to RecDer, and at the cellular level in vitro we will determine how both OD of lung tissue and repetitive RecDer of lung airspaces act individually and synergistically to damage the airway epithelium in epithelial cell monolayers grown on the inside of compliant tubes subjected to stretch and/or liquid bubble passage, respectively, 2) at the whole lung level in vivo we will determine how over-distension and RecDer lead to leak of proteinaceous fluid into the lung airspaces and cause derangements in lung mechanics and 3) we will determine how VILI can be minimized in a clinically relevant porcine surfactant deactivation model of heterogeneous ARDS subjected to a variety of modes of mechanical ventilation that apply differing relative degrees of tissue over-distention and RecDer. The data collected in Aims 1 and 2 will inform the development of a computational model that predicts how VILI develops over time as a result of the epithelial damage caused by RecDer and the exacerbating influences of overdistension. The model will be tested under clinically relevant conditions in Aim 3. These studies will establish the pathophysiologic understanding upon which personalized approaches to mechanical ventilation that minimize VILI can be developed for individual ARDS patients.