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（由申请方提供）：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。诸如肺炎、充血性心力衰竭和急性呼吸窘迫综合征（ARDS）的疾病的特征在于流体、蛋白质和细胞从肺循环运动到间质和肺泡空间。这种血管液体的渗出损害气体交换并引发导致急性肺衰竭的炎症事件级联。调节穿过肺血管膜的液体和细胞渗出的细胞信号传导途径在确定发生的肺损伤的程度和肺恢复所需的时间方面起着关键作用。利钠肽（NP）是一个蛋白质家族，在维持循环中适量的液体中起着至关重要的作用。NP响应于增加的血容量而从心脏释放，并用于增加血管的渗透性，从而促进流体、溶质和蛋白质从血管内渗出到全身血管床的间隙空间。然而，在肺循环中，纳米颗粒似乎可以防止急性肺损伤和肺水肿的形成。事实上，在动物模型和临床研究中，大量研究表明心房钠尿肽（ANP）可减轻急性肺损伤。NPs对血管通透性的这种差异性影响， 全身和肺血管床可以通过NP-受体作用的差异来解释。其他研究者先前的研究表明，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由NPR-C介导的。该提案将通过确定缺乏NPR-C的小鼠的肺损伤是否更严重以及NP是否不能保护NPR-C缺陷小鼠免受肺损伤来测试NPR-C保护免受急性肺损伤的假设。该提案还将确定肺血管内皮细胞的屏障功能是否可以通过增加或减少NPR-C表达来改变。其他研究旨在通过确定NPR-C的保护作用是否由G抑制蛋白（Gai）的激活和cAMP的下游调节介导，阐明负责NPR-C保护作用的下游信号传导途径。最后，将进行动物研究以确定体内NPR-C表达增加是否可以保护免受急性肺损伤。肺水肿的形成是急性呼吸衰竭重症病例发病和死亡的主要原因。识别负责维持完整肺内皮屏障功能的受体及其相关信号转导通路对于进一步理解肺通透性和开发急性肺损伤患者的新疗法至关重要。