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。几种机制涉及呼吸机诱导的肺损伤（VILI），特别是周期性气道塌陷和重开。推断数据支持周期性气道塌陷是VILI发生的一个重要因素，但它从未被明确记录。减少肺泡过度扩张和周期性气道关闭的策略降低了ARDS患者的死亡率，但与高碳酸中毒混淆，高碳酸中毒本身就是肺损伤的潜在调节剂。确定周期性气道塌陷的存在，通过姑息性干预措施消除它，以及与损伤的严重程度和分布的相关性，对于理解VILI和制定相关策略来预防它至关重要。本提案将评估机械通气诱导肺损伤的机制，并在仅由机械力引起的VILI兔模型中引发炎症。我将回答以下问题：1)周期性气道塌陷和重开是炎症的刺激因素吗？2)机械力在肺的什么部位和哪些细胞类型上发挥作用？3)我们能否明确记录周期性气道关闭？4)如果是这样，我们能否准确预测预防它的通风条件？5)非机械力（高碳酸血症）在VILI中起保护作用吗？方法：采用单克隆抗体ELISA法和免疫组织化学法测定炎症空间分布。通过血管外白蛋白积累和重力测量测量空间损伤。用雾化和灌注荧光微球测量区域V和Q。用多重惰性气体消除技术测量气体交换。用多次呼吸氮冲洗法测量通风异质性。目的1A：检查姿势改变和PEEP对损伤和炎症的严重程度和分布的影响。目的1B：确定VILI中引起炎症的解剖位置和细胞类型。目的2A：测量高碳酸血症对VILI期间肺损伤和炎症的影响。目的2B：探讨高碳酸血症如何改变低氧肺血管收缩和降低VILI。目的2C：研究高碳酸血症如何影响通气异质性和降低VILI。目的3A：通过局部通气分布的改变记录周期性气道塌陷和重开。目的3B：验证一种估计适当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.