Ventilator-Induced Lung Injury:Mechanisms & Consequences

机械通气是治疗呼吸衰竭的重要手段。然而，呼吸策略可能会引发或加重肺损伤。呼吸机诱导的肺损伤(VILI)涉及多种机制，特别是周期性的气道塌陷和再开放。推论数据支持周期性呼吸道塌陷是VILI发生的重要因素，但从来没有明确的文献记载。减少肺泡过度扩张和周期性呼吸道关闭的策略可以降低ARDS患者的死亡率，但会受到高碳酸血症的困扰，而高碳酸酸中毒本身就是肺损伤的潜在调节因素。确定周期性呼吸道塌陷的存在、通过姑息性干预消除它，以及与损伤的严重程度和分布的相关性，对于理解VILI和制定相关的预防策略至关重要。这项建议将评估机械通气在完全由机械力引起的VILI兔模型中诱导肺损伤和引发炎症的机制。我将回答以下问题：1)周期性的气道塌陷和重新打开炎症刺激？2)机械力在肺的哪个部位以及在哪些细胞类型上施加它们的影响？3)我们能明确地记录周期性的气道关闭吗？4)如果是，我们能否准确地预测防止它的呼吸条件？5)非机械力(高碳酸血症)在VILI中起保护作用吗？方法：用单抗酶联免疫吸附试验和免疫组织化学方法检测大鼠的空间炎症分布。通过血管外白蛋白蓄积和重量测量测量空间损伤。用雾化和灌流荧光微球测量区域V和Q。用多次惰性气体消除技术测量全球气体交换。用多次呼吸氮气冲洗法测量通风的异质性。目的1A：观察体位变化和PEEP对损伤和炎症的严重程度和分布的影响。目的1B：确定VILI炎症的解剖位置和细胞类型(S)。目的：测定VILI期间高碳酸血症对肺损伤和炎症反应的影响。目的2B：研究高碳酸血症如何改变缺氧性肺血管收缩和降低VILI。目的2C：研究高碳酸血症如何影响通气量的异质性和降低VILI。目的3A：通过区域通气量分布的变化记录周期性的气道塌陷和重新开放。目的3B：验证一种估计合适的PEEP水平以预防周期性呼吸道衰竭的方法。

Mechanical ventilation is an important tool in the management of respiratory failure. However, the ventilation strategy can initiate or exacerbate lung injury. Several mechanisms have been implicated in ventilator-induced lung injury (VILI), particularly cyclical airway collapse and reopening. Inferential data supports cyclical airway collapse as an important factor in the genesis of VILI, but it has never been definitively documented. Strategies minimizing alveolar over distension and cyclical airway closure decrease mortality in ARDS patients but are confounded by hypercapnic acidosis, itself a potential modulator of lung injury. Establishing the presence of cyclical airway collapse, its abolition with palliative interventions, and correlation with severity and distribution of injury is vital to understanding VILI and developing relevant strategies to prevent it. This proposal will evaluate mechanisms by which mechanical ventilation induces lung injury and initiates inflammation in a rabbit model of VILI caused solely by mechanical forces. I will address the following questions: 1) Is cyclical airway collapse and reopening a stimulus for inflammation? 2) Where in the lung and on which cell types do mechanical forces exert their effects? 3) Can we definitively document cyclical airway closure? 4) If so, can we accurately predict ventilatory conditions that prevent it? 5) Do non- mechanical forces (hypercapnia) play a protective role in VILI? Methods: Spatial inflammation distribution measured with monoclonal antibody ELISA and immunohistochemistry. Spatial injury measured by extravascular albumin accumulation and gravimetrics. Regional V and Q measured with aerosolized and perfused fluorescent microspheres. Global gas exchange measured with the multiple inert gas elimination technique. Ventilation heterogeneity measured with multiple breath nitrogen washout. Aim 1A: Examine how posture change and PEEP effect severity and distribution of injury and inflammation. Aim 1B: Determine the anatomical location and cell type(s) responsible inflammation in VILI. Aim 2A : Measure effects of hypercapnia on lung injury and inflammation during VILI. Aim 2B: Examine how hypercapnia alters hypoxic pulmonary vasoconstriction and reduces VILI. Aim 2C : Examine how hypercapnia effects ventilation heterogeneity and reduces VILI. Aim 3A: Document cyclical airway collapse and reopening via changes in regional ventilation distribution. Aim 3B: Validate a method to estimate appropriate PEEP level to prevent cyclical airway collapse.