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

NPR-C 在调节急性肺损伤中的作用

• 批准号: 9235305
• 负责人: Elizabeth O Harrington
• 金额: $ 30.25万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235305
• 关键词: Acute; Acute Lung Injury; Acute respiratory failure; Adenylate Cyclase; Adult Respiratory Distress Syndrome; Agonist; Air; Alveolar; Animal Model; Animals; Atrial Natriuretic Factor; Attenuated; Binding; Blood Circulation; Blood Vessels; Blood Volume; Brain natriuretic peptide; Cardiac; Cell Line; Cell Surface Receptors; Cells; Clinical Research; Congestive Heart Failure; Cyclic AMP; Cyclic GMP; Disease; Diuretics; Event; Extravasation; Failure; G-substrate; GTP-Binding Proteins; Gases; Guanylate Cyclase; Heart; Heart Atrium; Heart failure; Impairment; Inflammatory; Influenza A Virus, H1N1 Subtype; Laboratories; Ligands; Link; Lipopolysaccharides; Liquid substance; Lung; Lung diseases; Maintenance; Mediating; Membrane; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Movement; Mus; Natriuretic Peptides; Oxygen; Pathogenesis; Patients; Peptide Receptor; Peptides; Permeability; Physiological; Play; Pneumonia; Property; Protein Family; Proteins; Pseudomonas aeruginosa; Pulmonary Circulation; Pulmonary Edema; Refractory; Research Personnel; Respiratory Failure; Role; Sepsis; Shunt Device; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Systemic hypertension; Testing; Thinness; Thrombin; Time; Vascular Endothelial Cell; Vascular Permeabilities; Work; improved; in vivo; interstitial; lung injury; mortality; novel therapeutic intervention; novel therapeutics; pressure; protective effect; public health relevance; pulmonary vascular permeability; receptor; response; solute; treatment strategy; vascular bed

 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.

 描述（通过应用程序提供）：该提案旨在确定纳地钠肽受体-C（NPR-C）在缓解急性肺损伤中的作用。诸如肺炎，充血性心力衰竭和急性呼吸窘迫综合征（ARDS）之类的疾病的特征是流体，蛋白质和细胞从肺循环到间质和肺泡空间的运动。血管液的这种渗透会损害气体交换，并引发一系列炎症事件，导致急性肺衰竭。调节流体和跨肺血管膜细胞渗透的细胞信号通路在确定发生的肺损伤程度以及肺部恢复所需的时间方面起着关键作用。纳特里尿粉（NP）是蛋白质家族，在循环中保持适当量的液体中起着至关重要的作用。 NP从心脏释放，以响应增加的血容量并起作用以增加血管的渗透性，从而支持从血管内到全身血管床的间隙渗透，溶质和蛋白质的渗透。然而，在肺循环中，NP似乎可以预防急性肺损伤和肺水肿的增加。实际上，大量研究表明，在动物模型和临床研究中，心房尿尿肽（ANP）钝性急性肺损伤。 NP对血管通透性的这种差异作用 全身和肺血管床可以通过NP受体效应的差异来解释。其他研究者先前的研究表明，NPR-A介导了血管通透性的增强。但是，我们实验室的最新研究表明，NPS对急性肺损伤的保护作用是由NPR-C介导的。该提案将检验以下假设：NPR-C通过确定缺乏NPR-C的小鼠以及NPS无法预防NPR-C缺乏小鼠的肺损伤来保护急性肺损伤。该提案还将确定通过增加或降低NPR-C表达来改变肺血管内皮细胞中的屏障功能。其他研究旨在通过确定NPR-C的受保护作用是否通过激活G抑制性蛋白（GAI）和CAMP的下游调节来介导，以阐明负责NPR-C受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的表达是否增加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。鉴定接收器及其相关的信号转导途径，负责维持完整的肺内皮屏障功能，对于进一步了解我们对肺部渗透性的理解和为急性肺损伤患者开发新疗法至关重要。