MECHANICS OF ACUTE LUNG INJURY

描述（由申请人提供）：急性肺损伤（ALI）是危重患者的常见疾病，大约40%的病例是致命的。ALI患者的机械通气可能进一步损害肺，导致呼吸机诱导的肺损伤（VILI），其特征是液体从脉管系统渗漏到肺泡间隙，并伴有肺大面积塌陷。通常的做法是使用复盖手法——适当深度和持续时间的深度充气（Dl）来重新打开（复盖）萎陷的肺。然而，Dl - in的好处是短暂的，在严重的ALI中可能非常短暂。此外，Dl在有利于维持肺开放的同时，也增加了肺组织的应激，因此可能有利于VILI的发展。该建议的中心假设是，Dl的频率、持续时间和大小可以最佳地平衡肺开放量和VILI保护。该提案的总体目标是确定存在这样一个最佳的招募机制，它是特定于每个受试者的，并且可以从正在进行的肺力学测量中推断出来。我们将在小鼠ALI模型中验证这一概念，并将其转化为人类患者，具体目标有以下三个。具体目的1：建立深度充气的频率、幅度和持续时间如何决定ALI小鼠模型的肺力学和平均肺开放量。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。特异性目的3：将在小鼠ALI和VILI模型中获得的结果转化为人类患者。我们的研究结果有望导致基于生理的肺再生策略的设计，可以为ALI患者量身定制。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.