MECHANICS OF ACUTE LUNG INJURY

描述(由申请人提供)：急性肺损伤(ALI)是危重患者中常见的一种疾病，约40%的病例是致命的。对ALI患者进行机械通气可进一步损害肺，导致呼吸机诱导的肺损伤(VILI)，其特征是液体从血管渗漏到肺泡腔，并伴随肺大片塌陷。通常的做法是使用复张动作重新打开(复张)塌陷的肺--适当深度和持续时间的深度充气(DL)。然而，DL in的好处是暂时的，在严重的ALI中可能非常短暂。此外，DL虽然有利于开放肺的维持，但也增加了对肺组织的压力，因此可能有利于VILI的发展。这一建议的中心假设是，DL的提供频率、持续时间和大小可以最佳地平衡开放肺的数量和VILI的保护。该提案的总体目标是确定存在这样一个最佳的招募制度，它是针对每个对象的，并且可以从正在进行的肺力学测量中推断出来。我们将在ALI的小鼠模型中验证这一概念，并将这一概念翻译到人类患者身上，具体有三个目标。具体目的1：探讨深部充气的频率、幅度和持续时间如何决定ALI模型小鼠的肺力学和平均开放肺活量。具体目标2：确定深度通货膨胀的幅度、频率和持续时间如何导致VILI。具体目标3：将在ALI和VILI小鼠模型上获得的结果转化为人类患者。我们的研究结果有望引导设计基于生理的肺招募策略，该策略可以为ALI患者的个体量身定做。这将为未来的临床试验奠定基础。

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a common entity in critically ill people, and is fatal in roughly 40 percent of cases. Mechanical ventilation of patients with ALI may further damage the lung, leading to ventilator-induced lung injury (VILI) which is characterized by leakage of fluid from the vasculature into the alveolar spaces with concomitant collapse of large regions of the lung. It is common practice to re-open (recruit) collapsed lung using a recruitment maneuver - a deep inflation (Dl) of appropriate depth and duration. However, the benefits of a Dl in are transient, and can be very brief in severe ALI. Furthermore, while Dl's favor the maintenance of open lung, they also increase the stress applied to the lung tissues and so may favor the development of VILI. The central hypothesis of this proposal is that the Dl's can be delivered with a frequency, duration and magnitude that optimally balances the amount of open lung achieved against protection from VILI. The overall goals of the proposal is to establish that such an optimal recruitment regime exists, that it is specific to each subject, and that it can be deduced from ongoing measurements of pulmonary mechanics. We will verify this concept in mouse models of ALI and translate the concept to human patients, in the following three specific aims. Specific Aim 1: To establish how the frequency, magnitude and duration of deep inflations determine lung mechanics and the mean amount of open lung in mouse models of ALI. Specific Aim 2: To determine how the magnitude, frequency and duration of deep inflations lead to VILI. Specific Aim 3: To translate the results obtained in mouse models of ALI and VILI to human patients. The results of our studies are expected to lead to the design of physiologically-based lung recruitment strategies that can be tailored to the individual patient with ALI. This will set the stage for future clinical trials.