Preserving Epithelial Barrier Integrity in Ventilator-Induced Lung Injury

项目摘要 急性呼吸窘迫综合征（ARDS）的高死亡率是一个巨大的损失， 人的生命质量。目前还没有开发出治疗ARDS的药物， 纯粹的支持，因为病人在重症监护环境中接受护理。其中一个关键组成部分是 管理涉及机械通气。不幸的是，机械通气的压力和应变 可进一步损伤已经受损的肺组织，导致肺顺应性降低， 机械通气的压力急剧增加。这反过来又会在恶性循环中破坏组织。 这种循环往往最终是致命的。因此，本建议的中心前提是， 最重要的是，需要最小化VILI。我们先前的研究导致了过度假设， ARDS的发展仅发生一次肺单位的重复复张和去复张（RecDer） 引起上皮渗漏，使液体和蛋白质开始在空气中积聚。的 允许这一过程开始的后果是可怕的;表面活性剂功能受损，表面张力 并且组织应力增加，并且泄漏在恶性循环中无限加速。一旦 在进行中，该过程难以逆转并且由于肺组织的过度扩张（OD）而加剧， 这使得对于有发展成ARDS风险的患者来说避免它是至关重要的。我们的目标是全面测试 这一假设在体外和体内在一系列三个相关的模型系统：1）使用生物流体力学 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进行研究。 我们将确定肺组织的OD和肺空间的重复RecDer如何单独起作用， 协同地损伤在顺应性的内部上生长的上皮细胞单层中的气道上皮 分别经受拉伸和/或液体气泡通过的管，2）在体内的整个肺水平，我们将 确定过度扩张和RecDer如何导致蛋白质液体泄漏到肺气隙中， 导致肺力学紊乱，3）我们将确定如何在临床上最大限度地减少VILI， 相关的猪表面活性剂失活模型的异质性ARDS进行了各种模式的 机械通气应用不同的相对程度的组织过度扩张和RecDer。数据 目标1和2中收集的信息将为预测VILI如何 随着时间的推移，由于RecDer引起的上皮损伤以及 过度膨胀将在目标3中的临床相关条件下对模型进行测试。这些研究将 建立病理生理学的理解， 可以为个体ARDS患者开发最小化VILI的方法。

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.