Ventilation Improves Lung Physiology and Biology

描述（由申请人提供）：据信，在机械通气（MV）期间，肺单元的过度膨胀和/或在塌陷气道和肺泡不张区域反复打开和关闭过程中产生的剪切力会加剧，甚至可能引发肺损伤，导致炎症，并可能导致多系统器官衰竭。最近，我们报道了在一个啮齿动物急性肺损伤模型中，在一个周期的基础上增加潮汐量（Vt）和频率的可变性，称为可变通气（VV），可以改善肺力学和氧合。此外，接受VV的健康豚鼠与接受常规MV的豚鼠相比，肺泡内表面活性剂含量增加，血浆蛋白和细胞因子水平降低。这表明VV不仅能诱导内源性表面活性剂释放，还能减轻呼吸机引起的肺损伤和炎症。基于这些观察结果，我们提出了以下两个主要假设：1)与目前公认的低Vt通气策略相比，VV通过改善肺泡招募，减少细胞损伤、炎症和细胞因子释放，增强了肺对VILI发展的保护；2) VV的可变性量可以“调节”，使得应用于肺泡上皮的拉伸模式有助于刺激表面活性剂的产生并最大化表面活性剂的释放，同时最大限度地降低损伤上皮和产生炎症的风险。为了验证这些假设，我们设定了三个具体目标：1)确定以力学、气体交换和表面活性剂组成为特征的肺功能作为正常豚鼠VV变异性和呼气末正压的函数。基本原理：本目的目的是测试在长期通气过程中，逐渐增加MV变异性是否能改善肺的生理和生物反应，以及是否存在与肺压力-容积曲线相关的最佳变异性水平，在该水平上力学、气体交换和表面活性剂成分受到的损害最小。将测量力学、血气、表面活性剂成分，并从肺结构变异性的组织病理学评估中评估肺损伤的数量和异质性。2)确定内毒素致急性肺损伤啮齿动物模型中是否可能存在类似的力学、气体交换和表面活性剂组成优化。基本原理：这一目的将使我们能够测试VV是否也能有效地降低原有肺损伤恶化的风险。3)观察VV赋予肺泡上皮的可变拉伸模式是否刺激了磷脂（PL）和表面活性剂蛋白（SP）的产生和分泌。原理：通过测量PL和SP水平以及适当的RNA水平，我们将确定VV的机械拉伸模式是否刺激基因表达。意义：如果VV能够最大限度地减少机械力对肺泡室的有害影响，同时刺激表面活性剂的上调，那么VV将在本质上提供一种简单的机械通气策略，能够诱导治疗性的“内源性表面活性剂替代”。

DESCRIPTION (provided by applicant): It is believed that during mechanical ventilation (MV), over-distension of lung units and/or shear forces generated during repetitive opening and closing of collapsed airways and atelectatic alveolar regions can exacerbate and may even trigger lung injury leading to inflammation and potentially to multiple-system organ failure. Recently, we have reported that during MV, variability added to tidal volume (Vt) and frequency on a cycle by cycle basis, called variable ventilation(VV), improves both lung mechanics and oxygenation in a rodent model of acute lung injury. Furthermore, healthy guinea pigs that underwent VV exhibited increased surfactant content and reduced plasma proteins and cytokine levels within the alveolar space compared to those that received conventional MV. This suggests that not only did VV induce endogenous surfactant release, but also served to reduce ventilator induced lung injury and inflammation in this animal model. Based on these observations, we formulate the following two primary hypotheses of this proposal: 1) Compared to the currently accepted low Vt ventilation strategy, VV provides an increased protection of the lung against the development of VILI by improving alveolar recruitment, which decreases cellular damage, inflammation and cytokine release; and 2) The amount of variability in VV can be "tuned" such that the stretch patterns applied to alveolar epithelium serve to stimulate surfactant production and maximize surfactant release while minimizing the risks of damaging the epithelium and generating inflammation. To test these hypotheses, we set up three specific aims: 1) To determine lung function characterized by mechanics, gas exchange and surfactant composition as a function of the variability included in VV and the positive end-expiratory pressure in normal guinea pigs. Rationale: This aim will test whether gradually adding variability to MV improves the physiological and biological response of the lung during long-term ventilation and whether there exists an optimal level of variability in relation to the pressure-volume curve of the lung at which mechanics, gas exchange, and surfactant composition are least compromised. Mechanics, blood gases, surfactant composition will be measured and the amount and heterogeneity of lung injury will be assessed from histopathological evaluation of the lung structure as a function of variability. 2) To determine whether a similar optimization of mechanics, gas exchange and surfactant composition is possible in a rodent model of endotoxin-induced acute lung injury. Rationale: This aim will allow us to test whether VV is also effective in minimizing the risk of exacerbation of pre-existing lung injury. 3) To determine whether the variable stretch pattern imparted by VV on the alveolar epithelium stimulates the production and secretion of phospholipids (PL) and surfactant proteins (SP). Rationale: By measuring PL and SP levels together with the appropriate RNA levels, we will determine whether the mechanical stretch patterns in VV stimulate gene expression or not. Significance: If VV is able to minimize the deleterious effects of mechanical forces on the alveolar compartment while simultaneously stimulate upregulation of surfactant, then VV will, in essence, provide a simple mechanical ventilation strategy capable of inducing therapeutic "endogenous surfactant replacement."