Mechanical Injury of the Alveolar Epithelium

这项研究计划的广泛的长期目标是预防或减轻肺气压伤的影响。 4%到15%的通气患者会因气压伤而发生气胸，气压伤是一种与机械通气产生的高压或高压相关的肺损伤。 除了气胸，气压伤的一个容易识别的标志，最近的证据表明，机械通气可能会引起肺液体平衡和血气屏障通透性的深刻变化。 实验表明，肺损伤实际上与高容量而不是高压更密切相关，这表明肺实质精细结构的变形对损伤有重要贡献。 在第一个资助期内，证实了肺的肺泡上皮衬里易受大幅度动态变形损伤的假设，与机械通气期间经历的损伤相当，这些发现得到了最近临床研究的支持，这些研究表明低潮气量通气可显著降低死亡率。 这些发现强调了实验模型的重要性，以确定机制，使上皮细胞易受机械变形，并定义干预措施，保护上皮细胞免受机械变形。使用我们建立的VILI体外模型，我们建议在细胞和分子水平上扩展我们对变形诱导的上皮损伤的理解。研究计划的总体假设是机械应变是VILI中急性肺泡上皮功能改变的主要原因。该5年计划的短期目标是：I）测量与细胞旁（Aim I）和跨细胞（Aim 2）上皮转运改变相关的菌株，以及2）确定负责细胞内机械信号转导的分子途径（Aim 3）。 因此，拟议的研究计划将为开发预防或改善VILI的药物治疗奠定基础。 计划中的实验研究对于实现我们的长期目标至关重要，即开发更安全，更有效的机械通气模式和新的干预策略，以预防由于上皮过度扩张导致的急性VILI。

The broad long-term objective of this research proposal is to prevent or lessen the effects of pulmonary barotrauma. Four to fifteen percent of ventilated patients experience pneumothorax due to barotrauma, a lung injury associated with high pressures or volumes produced by mechanical ventilation. In addition to pneumothorax, an easily-recognized hallmark of barotrauma, recent evidence suggests that mechanical ventilation may induce profound changes in lung fluid balance and blood-gas barrier permeability. Experiments have shown that lung injury is actually more closely associated with high volumes rather than high pressures, suggesting that deformation of the fine structure of the lungs parenchyma makes a critical contribution to the injury. During the first period of funding, the hypothesis that the alveolar epithelial lining of the lung is vulnerable to injury from large-amplitude dynamic deformations, comparable to those experienced during mechanical ventilation was confirmed, and these findings were supported by recent clinical studies demonstrating a significant reduction in mortality with low tidal volume ventilation. These findings emphasize the importance of experimental models to determine the mechanisms that make the epithelium susceptible to mechanical deformation, and to define interventions that protect the epithelium against mechanical deformation. Using our established in vitro model for VILI, we propose to extend our understanding of deformation-induced epithelial injury at the cellular and molecular level. The overall hypothesis of the research plan is that mechanical strain is the primary cause of acute alveolar epithelial functional alterations in VILI. The short-term objectives of this 5-year plan are I) to measure the strains associated with alterations in paracellular (Aim I) and transcellular (Aim 2) epithelial transport, and 2) to determine molecular pathways responsible for transducing mechanical signals within the cell (Aim 3). Thus, the proposed research plan will lay the foundation for the development of pharmacological therapies to prevent or ameliorate VILI. The planned experimental studies are essential to address our long-term goal of developing safer, more effective mechanical ventilator modes and new intervention strategies to prevent acute VILI due to epithelial over-distention.