Role of LUBAC and Na K-ATPase in Acute Lung Injury

项目总结 急性肺损伤和急性呼吸窘迫综合征(ARDS)患者气体交换受损 由于肺泡上皮功能改变，导致水肿液积聚，导致缺氧。 肺泡缺氧在ARDS患者中很常见，并导致肺泡上皮功能障碍。季节性 流感感染影响了美国和世界各地相当大比例的人口，以及 虽然大多数感染甲型流感的患者康复后没有后遗症，但在一些患者中，流感病毒 感染可能会导致严重的肺炎和ARDS。肺泡上皮细胞是甲型流感病毒的靶细胞， 并在安装初始主机响应方面发挥重要作用。在甲型流感病毒感染时，肺泡 上皮细胞释放的细胞因子有助于单核细胞和巨噬细胞在部位的募集 并参与病毒清除，这可能会限制感染的传播。然而， 这些事件的潜在机制还没有完全弄清楚。我们假设除了它的 肺泡上皮具有屏障功能，在保护肺免受严重损伤中起着重要的作用。 受伤。这项赠款提案的第一个目的是试图阐明导致稳定的机制 Na，K-ATPase在低氧期间的质膜水平作为对应激的一种适应，从而促进细胞存活。 我们将研究蛋白激酶Cζ的降解是否会触发E3对Na，K-ATPase的下调 连接酶HOIL-1L可减少慢性低氧时肺泡上皮细胞死亡和肺损伤。HOIL-1L是一种 线性泛素化组装复合体(LUBAC)的成员。在为第二个具体问题提出的研究中 目的：探讨LUBAC是否参与肺组织炎症强度的调节。 流感病毒感染过程中的上皮细胞。第三个具体目标是检查通过哪些机制 细胞内钠浓度升高，这发生在Na，K-ATPase受到适度抑制时， 阻止肺泡上皮细胞病毒复制以及药物对Na，K-ATPase的抑制 强心类固醇如哇巴因和地高辛代表了一种通过抑制病毒的保护机制 复制。低氧和低氧致肺泡上皮功能障碍的机制(S) 流感病毒感染将提供具有临床相关性的新信息，并有可能 急性肺损伤患者的创新治疗方法。

PROJECT SUMMARY Patients with acute lung injury and Acute Respiratory Distress Syndrome (ARDS) have impaired gas exchange due to altered alveolar epithelial function, which results in accumulation of edema fluid leading to hypoxia. Alveolar hypoxia is common in patients with ARDS and contributes to alveolar epithelial dysfunction. Seasonal influenza infection affects a significant proportion of the population in the United States and worldwide, and while most patients infected with influenza A recover without sequelae, in some patients influenza virus infection may cause severe pneumonitis and ARDS. Alveolar epithelial cells are targets for influenza virus A, and play an important role in mounting the initial host response. Upon influenza A virus infection, alveolar epithelial cells release cytokines that contribute to the recruitment of monocytes and macrophages to the site of infection and also participate in viral clearance, which may limit the infection from spreading. However, the underlying mechanisms of these events are not completely understood. We hypothesize that in addition to its barrier function, the alveolar epithelium plays an important effector role in protecting the lung from severe injury. The first aim of this grant proposal seeks to elucidate the mechanisms that lead to the stabilization of Na,K-ATPase plasma membrane levels during hypoxia as an adaptation to stress, thus promoting cell survival. We will study whether the degradation of PKCζ, which triggers the down-regulation of Na,K-ATPase, by the E3 ligase HOIL-1L decreases alveolar epithelial cell death and lung injury during chronic hypoxia. HOIL-1L is a member of the Linear Ubiquitination Assembly Complex (LUBAC). In studies proposed for the second specific aim, we will assess whether LUBAC participates in the modulation of the inflammatory intensity in the lung epithelium during influenza virus infection. The third specific aim examines the mechanisms by which increased intracellular sodium concentration, which occurs during modest inhibition of the Na,K-ATPase, prevents viral replication in alveolar epithelial cells and whether pharmacologic inhibition of the Na,K-ATPase by cardiotonic steroids such as ouabain and digoxin represents a protective mechanism by inhibiting virus replication. Understanding the mechanism(s) that lead to alveolar epithelial dysfunction caused by hypoxia and influenza virus infection will provide novel information that is of clinical relevance and has the potential for innovative approaches in the treatment of patients with acute lung injury.