Dissecting the molecular mechanisms of lung injury during mechanical ventilation

项目摘要 急性呼吸窘迫综合征（ARDS）是一种致命的疾病，其特征是快速发作， 低氧血症和呼吸衰竭。ARDS患者的主要治疗是支持性护理， 机械通气（MV）。虽然可以挽救生命，但机械通气会加剧肺损伤，甚至 造成新生损伤，称为呼吸机诱导的肺损伤（VILI）。VILI是由机械力引起的， MV包括过度拉伸（体积创伤）、过度压力（气压创伤）和由于反复 肺单位萎陷和重新开放（肺不张）。这些机械的分子机制 力加剧肺损伤仍然知之甚少。临床医生试图通过监测气道来预防VILI 压力和使用低潮气量，但即使这些参数在“安全”范围内，损伤仍然存在。 目前，还没有药物疗法可以预防或治疗ARDS患者的VILI。mTORC1是一种 细胞生长和脂质代谢的中心调节器。与mTORC1的典型激活相反， 在有利的生长条件下，我们最近发现mTORC 1在肺上皮细胞中被激活， 有害的机械通气。我们还发现，药理学mTORC 1抑制可防止肺损伤， 进行机械通气我们假设mTORC 1激活在介导VILI中起着核心作用， 并且代表了ARDS中的新的治疗靶点。我们将确定mTORC1 使用在I型和II型肺泡上皮细胞中具有mTORC 1失活的小鼠， 以及人肺中机械通气的新型体外模型。在目标1中，我们将确定如何 mTORC1激活诱导呼吸机诱导的肺损伤期间的表面活性剂功能障碍。在目标2中， 确定mTORC 1调节损伤后上皮膜修复的机制， 机械通气在目标3中，我们将使用利用机械通气的临床相关的2次打击模型 在脓毒症或流感性肺炎引起的肺损伤后，检测mTORC 1抑制预防肺损伤的功效。 Vili在ARDS。我们的研究将深入了解mTORC 1激活如何损害表面活性剂， 功能和膜修复过程中VILI，并将确定新的药物靶点与ARDS患者。

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.