Dissecting the molecular mechanisms of lung injury during mechanical ventilation

剖析机械通气期间肺损伤的分子机制

• 批准号: 10352404
• 负责人: Joshua A Englert
• 金额: $ 54.89万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352404
• 关键词: Acute Respiratory Distress Syndrome; Alveolar; Annexins; Attenuated; Binding; Binding Proteins; Blood; Blood capillaries; Breathing; Cell Death; Cell membrane; Cell physiology; Cells; Complex; Data; Dysbarism; Epithelial; Epithelial Cells; FRAP1 gene; Fluorescent Dyes; Functional disorder; Genetic; Growth; Human; Hypoxemia; Impairment; Inflammation; Injury; Intensive Care Units; Knockout Mice; Life; Lung; Lung Compliance; Measures; Mechanical ventilation; Mediating; Membrane; Modeling; Molecular; Monitor; Multiprotein Complexes; Mus; Oxygen; Patients; Permeability; Pharmacology; Phospholipids; Phosphorylation; Physiology; Play; Pre-Clinical Model; Protein-Serine-Threonine Kinases; Research; Respiratory Failure; Role; Savings; Sepsis; Stretching; Supportive care; System; Tidal Volume; Ventilator; Ventilator-induced lung injury; Volutrauma; alveolar epithelium; atelectrauma; cecal ligation puncture; cell growth; clinically relevant; efficacy testing; in vitro Model; in vivo; influenza pneumonia; inhibitor; lipid metabolism; live cell microscopy; lung injury; mechanical force; new therapeutic target; novel; novel strategies; pre-clinical; pressure; prevent; repaired; seal; surfactant; surfactant function; trafficking

Project Summary The acute respiratory distress syndrome (ARDS) is a deadly condition characterized by the rapid onset of hypoxemia and respiratory failure. The mainstay of therapy for ARDS patients is supportive care with mechanical ventilation (MV). Although life-saving, mechanical ventilation can exacerbate lung injury and even cause de novo injury, known as ventilator induced lung injury (VILI). VILI arises from mechanical forces during MV including excessive stretch (volutrauma), excessive pressure (barotrauma), and injury due to repeated collapse and reopening of lung units (atelectrauma). The molecular mechanisms by which these mechanical forces exacerbate lung injury remain poorly understood. Clinicians try to prevent VILI by monitoring airway pressures and using low tidal volumes, but injury persists even when these parameters are in a “safe” range. Currently, there are no pharmacologic therapies to prevent or treat VILI in patients with ARDS. mTORC1 is a central regulator of cell growth and lipid metabolism. In contrast to canonical activation of mTORC1 under favorable growth conditions, we recently discovered that mTORC1 is activated in lung epithelial cells following injurious mechanical ventilation. We also found that pharmacologic mTORC1 inhibition prevents lung injury during mechanical ventilation. We hypothesize that mTORC1 activation plays a central role in mediating VILI and represents a novel therapeutic target in ARDS. We will determine the mechanisms by which mTORC1 inhibition prevents VILI using mice with mTORC1 inactivation in type I and type II alveolar epithelial cells as well as novel in vitro models of mechanical ventilation in the human lung. In Aim 1 we will identify how mTORC1 activation induces surfactant dysfunction during ventilator induced lung injury. In Aim 2 we will identify the mechanisms by which mTORC1 regulates epithelial membrane repair following injurious mechanical ventilation. In Aim 3 we will use clinically relevant 2-hit models that utilize mechanical ventilation following lung injury from sepsis or influenza pneumonia to test the efficacy of mTORC1 inhibition to prevent VILI in ARDS. Our studies will provide an in-depth understanding of how mTORC1 activation impairs surfactant function and membrane repair during VILI and will identify novel drug targets for patients with ARDS.

项目摘要 急性呼吸窘迫综合征(ARDS)是一种致命的疾病，其特征是迅速发作 低氧血症和呼吸衰竭。ARDS患者的主要治疗方法是支持性护理 机械通气组。虽然机械通气可以挽救生命，但它会加重肺损伤，甚至 引起新生损伤，称为呼吸机诱导肺损伤(VILI)。Vili是由机械力在 MV包括过度拉伸(气囊创伤)、过度压力(气压创伤)和重复损伤 肺单位的塌陷和重新开放(肺不张创伤)。这些机械的分子机制 加重肺损伤的力量仍然知之甚少。临床医生试图通过监测呼吸道来预防VILI 使用低潮气量和压力，但即使在这些参数处于“安全”范围时，伤害仍然存在。 目前，还没有预防或治疗ARDS患者VILI的药物疗法。MTORC1是一种 细胞生长和脂类代谢的中央调节器。与mTORC1在下面的规范激活相反 在良好的生长条件下，我们最近发现mTORC1在下列肺上皮细胞中被激活 有害的机械通风。我们还发现，抑制mTORC1的药理作用可以预防肺损伤 在机械通风过程中。我们推测mTORC1激活在VLI的调节中起核心作用 代表了ARDS的一个新的治疗靶点。我们将确定mTORC1通过哪些机制 抑制用mTORC1失活的小鼠肺泡上皮细胞I和II作为预防VILI的方法 以及人类肺部机械通风的新的体外模型。在目标1中，我们将确定如何 呼吸机所致肺损伤时mTORC1激活可导致肺表面活性物质功能障碍。在《目标2》中我们将 确定mTORC1调节损伤后上皮膜修复的机制 机械通风。在目标3中，我们将使用临床上相关的两次击打模式，利用机械通风。 败血症或流感肺炎致肺损伤后检测mTORC1抑制预防的效果 维利在ARDS。我们的研究将提供对mTORC1激活如何损害表面活性物质的深入理解。 VILI期间的功能和膜修复，并将为ARDS患者确定新的药物靶点。