Ventilation Improves Lung Physiology and Biology

描述(申请人提供)：据认为，在机械通气(MV)过程中，在反复打开和关闭塌陷的呼吸道和肺泡不张区域时产生的肺单位过度膨胀和/或剪切力会加剧，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MV期间，潮气量(Vt)和频率的变异性增加了一个周期的潮气量(Vt)和频率，称为可变通气法(Vv)，可以改善急性肺损伤啮齿动物模型的肺力学和氧合。此外，与接受常规机械通气的豚鼠相比，接受VV的健康豚鼠的肺表面活性物质含量增加，肺泡间隙内的血浆蛋白质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物质的释放，而且能减轻呼吸机诱导的肺损伤和炎症反应。基于这些观察，我们对这一建议提出了以下两个主要假设：1)与目前公认的低Vt通风策略相比，Vv通过改善肺泡复张来增强对VILI的保护，从而减少细胞损伤、炎症和细胞因子的释放；以及2)Vv的变化量可以“调节”，以便应用于肺泡上皮的拉伸模式有助于刺激表面活性物质的产生，并最大限度地释放表面活性物质，同时将破坏上皮和产生炎症的风险降至最低。为了验证这些假说，我们设立了三个具体目标：1)测定正常豚鼠的肺功能，包括机械性能、气体交换和表面活性物质组成，作为VV变异性和呼气末正压的函数。理论基础：这一目标将检验在长期的机械通气过程中，是否逐渐增加变异性以改善肺的生理和生物反应，以及是否存在与肺的压力-容量曲线相关的最佳变异性水平，在该变异性水平下，机械、气体交换和表面活性物质的组成受到的影响最小。力学、血气、表面活性成分将被测量，肺损伤的数量和异质性将通过肺结构的组织病理学评估作为变异性的函数来评估。2)确定在内毒素诱导的急性肺损伤的啮齿动物模型中，是否有可能对力学、气体交换和表面活性物质组成进行类似的优化。理论基础：这一目标将使我们能够测试VV是否也有效地将先前存在的肺损伤恶化的风险降至最低。3)探讨VV对肺泡上皮细胞施加的可变拉伸模式是否刺激磷脂(PL)和表面活性蛋白(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中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，同时刺激表面活性物质的上调，那么VV本质上将提供一种简单的机械通气策略，能够诱导治疗性的“内源性表面活性物质替代”。

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."