The Role of NPR-C In Modulation Of Acute Lung Injury

 描述(申请人提供)：本提案旨在确定利钠肽受体-C(NPR-C)在减轻急性肺损伤中的作用。肺炎、充血性心力衰竭和急性呼吸窘迫综合征(ARDS)等疾病的特征是液体、蛋白质和细胞从肺循环移动到间质和肺泡腔。这种血管液体的渗出损害了气体交换，并引发了一连串的炎症事件，导致急性肺衰竭。调节肺血管膜上液体和细胞渗出的细胞信号通路在决定肺损伤发生的程度和肺恢复所需时间方面起着关键作用。利钠肽(NP)是一个蛋白质家族，在维持血液循环中适量的液体方面起着至关重要的作用。随着血容量的增加，NPs从心脏中释放出来，增加血管的通透性，从而促进液体、溶质和蛋白质从血管内渗出到全身血管床的间质空间。然而，在肺循环中，NPs似乎对增加的急性肺损伤和肺水肿形成具有保护作用。事实上，在动物模型和临床研究中，大量研究表明心钠素(ANP)可以钝化急性肺损伤。NPs对血管通透性的不同影响 全身和肺血管床可以通过NP受体作用的不同来解释。其他研究人员之前的研究表明，血管通透性的增强是由NPR-A介导的。然而，我们实验室最近的研究表明，NPs对急性肺损伤的保护作用是通过NPR-C介导的。这项建议将通过确定缺乏NPR-C的小鼠的肺损伤是否更严重，以及NPR-C缺乏的小鼠是否未能保护肺损伤来检验NPR-C预防急性肺损伤的假设。该提案还将确定是否可以通过增加或减少NPR-C的表达来改变肺血管内皮细胞的屏障功能。其他研究旨在通过确定NPR-C的保护作用是否通过激活G-抑制蛋白(GAI)和下游调节cAMP来阐明NPR-C的保护作用的下游信号通路。最后，将进行动物研究，以确定体内NPR-C表达增加是否可以预防急性肺损伤。在严重的急性呼吸衰竭病例中，肺水肿的形成是发病率和死亡率的主要原因。识别负责维持完整的肺内皮细胞屏障功能的受体及其相关的信号转导通路，对于加深我们对肺通透性的了解和开发治疗急性肺损伤的新方法至关重要。

 DESCRIPTION (provided by applicant): This proposal aims to determine the role of natriuretic peptide receptor-C (NPR-C) in mitigating acute lung injury. Diseases such as pneumonia, congestive heart failure, and acute respiratory distress syndrome (ARDS) are characterized by movement of fluid, protein and cells from the pulmonary circulation to the interstitial and alveola space. This transudation of vascular fluid impairs gas exchange and initiates a cascade of inflammatory events that leads to acute lung failure. Cell signaling pathways that regulate fluid and cellular transudation across the pulmonary vascular membrane play critical roles in determining the extent of lung damage that occurs and the time it takes for the lung to recover. The natriuretic peptides (NP) are a family of proteins that play critically important roles in maintaining appropriate amounts of fluid in the circulation. NPs are released from the heart in response to increased blood volume and act to increase the permeability of blood vessels, thereby facilitating transudation of fluid, solutes and proteins from the intravascular to the interstitial space of systemic vascular beds. In the pulmonary circulation, however, NPs appear to protect against increased acute lung injury and pulmonary edema formation. In fact, numerous studies have shown that atrial natriuretic peptide (ANP) blunts acute lung injury in animal models and clinical studies. This differential effect of NPs on vascular permeability in the systemic and pulmonary vascular beds may be explained by differences in effects of the NP-receptors. Previous studies by other investigators suggest that enhancement of vascular permeability is mediated by NPR-A. However, recent studies from our laboratory suggest that the protective effects of NPs on acute lung injury are mediated by NPR-C. This proposal will test the hypothesis that NPR-C protects against acute lung injury by determining if lung injury is worse in mice lacking NPR-C and if NPs fail to protect against lung injury in NPR-C deficient mice. The proposal will also determine if barrier function in pulmonary vascular endothelial cells can be altered by increasing or decreasing NPR-C expression. Other studies aim to elucidate downstream signaling pathways responsible for the protective effects of NPR-C by determining if the protective effect of NPR-C is mediated by activation of G-inhibitory protein (Gai) and downstream modulation of cAMP. Finally, animal studies will be performed to determine if increased expression of NPR-C in vivo can protect against acute lung injury. Pulmonary edema formation is the primary cause of morbidity and mortality in severe cases of acute respiratory failure. Identification of receptors and their associated signal transduction pathways responsible for maintenance of intact pulmonary endothelial barrier function is vital to furthering our understanding of pulmonary permeability and developing new therapies for patients with acute lung injury.