Ventilator-Induced Lung Injury:Mechanisms & Consequences

呼吸机引起的肺损伤：机制

• 批准号: 6638166
• 负责人: SCOTT E SINCLAIR
• 金额: $ 12.85万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6638166
• 关键词: albumins; breath tests; cell type; diagnostic respiratory lavage; enzyme linked immunosorbent assay; hypercapnia; iatrogenic disease; immunocytochemistry; inflammation; interleukin 8; laboratory rabbit; lung injury; myeloperoxidase; oximetry; posture; radioactive microsphere technique; respirators; respiratory airflow disorder; thermogravimetry; tumor necrosis factor alpha; vasoconstriction

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.

机械通气是治疗呼吸衰竭的重要工具。然而，通气策略可能引发或加剧肺损伤。呼吸机引起的肺损伤（VILI）涉及多种机制，特别是周期性气道塌陷和重新开放。推断数据支持周期性气道塌陷是 VILI 发生的一个重要因素，但从未得到明确记录。尽量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，但会受到高碳酸血症的影响，高碳酸血症本身是肺损伤的潜在调节因素。确定周期性气道塌陷的存在、通过姑息性干预措施消除气道塌陷，以及与损伤严重程度和分布的相关性，对于了解 VILI 并制定相关预防策略至关重要。该提案将评估机械通气在仅由机械力引起的 VILI 兔子模型中诱发肺损伤并引发炎症的机制。我将回答以下问题：1）周期性气道塌陷和重新开放是否会刺激炎症？ 2) 机械力在肺部的哪个部位以及哪些细胞类型上发挥作用？ 3）我们能明确记录周期性气道关闭吗？ 4）如果是这样，我们能否准确预测阻止其发生的通气条件？ 5) 非机械力（高碳酸血症）对 VILI 起到保护作用吗？方法：用单克隆抗体ELISA和免疫组织化学测量炎症的空间分布。通过血管外白蛋白积累和重量分析测量空间损伤。使用雾化和灌注荧光微球测量区域 V 和 Q。采用多重惰性气体消除技术测量全局气体交换。通过多次呼吸氮气冲洗测量通气不均匀性。目标 1A：检查姿势变化和 PEEP 如何影响损伤和炎症的严重程度和分布。目标 1B：确定 VILI 中炎症的解剖位置和细胞类型。目标 2A：测量 VILI 期间高碳酸血症对肺损伤和炎症的影响。目标 2B：检查高碳酸血症如何改变缺氧性肺血管收缩并减少 VILI。目标 2C：检查高碳酸血症如何影响通气不均匀性并减少 VILI。目标 3A：通过区域通风分布的变化记录周期性气道塌陷和重新开放。目标 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。