Ventilator-Induced Lung Injury:Mechanisms & Consequences

机械通气是治疗呼吸衰竭的重要手段。然而，通气策略可引发或加重肺损伤。呼吸机诱导的肺损伤（VILI）涉及几种机制，特别是周期性气道塌陷和重新开放。推理数据支持周期性气道塌陷是VILI发生的一个重要因素，但从未明确记录。最大限度地减少肺泡过度扩张和周期性气道关闭的策略可降低ARDS患者的死亡率，但会被高碳酸血症（本身是肺损伤的潜在调节因子）所混淆。建立存在的周期性气道塌陷，其废除姑息性干预措施，并与损伤的严重程度和分布的相关性是至关重要的了解VILI和制定相关的战略，以防止it.This建议将评估机制，机械通气诱导肺损伤，并启动在兔模型VILI引起的炎症完全由机械力。我将解决以下问题：1）周期性气道塌陷和重新开放是否刺激炎症？2)机械力作用于肺的什么部位和哪些细胞类型？3)我们能明确记录周期性气道关闭吗？4)如果是这样的话，我们能准确地预测预防它的条件吗？5)非机械力（高碳酸血症）是否在VILI中起保护作用？方法：采用单克隆抗体ELISA和免疫组化方法检测大鼠腹腔内炎症分布。通过血管外白蛋白积聚和重量测定法测量空间损伤。区域V和Q测量雾化和灌注荧光微球。用多重惰性气体消除技术测量总气体交换。通过多次呼吸氮洗脱测量通气异质性。目的1A：研究体位改变和PEEP如何影响损伤和炎症的严重程度和分布。目的1B：确定VILI中引起炎症的解剖位置和细胞类型。目的2A：测量VILI期间高碳酸血症对肺损伤和炎症的影响。目的2B：检测高碳酸血症如何改变缺氧性肺血管收缩并降低VILI。目的2C：检查高碳酸血症如何影响通气异质性并降低VILI。目的3A：通过局部通气分布的变化记录周期性气道塌陷和重新开放。目的3B：提供一种估算适当PEEP水平以防止周期性气道塌陷的方法。

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.