S-nitrosothiol-regulated pathways in acute lung injury

急性肺损伤中 S-亚硝基硫醇调节途径

• 批准号: 8030572
• 负责人: Matthew Wolf Foster
• 金额: $ 19.63万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8030572
• 关键词: Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Affect; Alveolar; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Biological Markers; Breathing; Bronchoalveolar Lavage Fluid; Data; Development; Diffuse; Epithelial Cells; Gases; Gene Proteins; Immune response; In Vitro; Incidence; Inflammation; Inflammatory; Injury; Lipopolysaccharides; Liquid substance; Lung; Mass Spectrum Analysis; Measures; Mediator of activation protein; Molecular Target; Mus; Natural Immunity; Nitric Oxide; Pathway interactions; Patients; Peptides; Physiological; Pneumonia; Post-Translational Protein Processing; Prevention therapy; Property; Protein Analysis; Protein S; Proteins; Proteome; Proteomics; Regulation; Resolution; Respiratory Failure; Risk; Role; S-Nitrosothiols; Saline; Sepsis; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; Structure of respiratory epithelium; Supportive care; TLR4 gene; Therapeutic; Translating; Trauma; United States; airway epithelium; airway inflammation; base; chemokine; design; effective therapy; ethyl nitrite; lung injury; mortality; mouse model; prevent; protein expression; research study; respiratory; response; transcription factor

DESCRIPTION (provided by applicant): Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by an initial airway inflammatory insult that results in diffuse alveolar damage and the subsequent development of respiratory failure. Despite an incidence of ~200,000 cases/year in the United States and mortality rate approaching 40%, no effective therapy exists to treat ALI/ARDS. S-nitrosothiols (SNOs) are endogenously-produced, bioactive forms of nitric oxide that function to inhibit immune response pathways in the respiratory epithelium. Recently, we demonstrated that airway SNOs are acutely depleted in a mouse model of ALI and that treatment with inhaled ethyl nitrite (ENO), an S-nitrosylating agent, protects from the development of lung injury. However, the molecular targets of SNOs in the lung airway remain to be discerned. We hypothesize that proteomic signatures derived from analysis of airway lining fluid can be used to elucidate the SNO-regulated immune response pathways in ALI which underlie the pharmacological basis of ENO therapy. Accordingly, we propose to: 1. Characterize the effects of ENO treatment on the airway proteome in ALI and identify signaling pathways that are affected by SNO repletion; and 2. Identify BALF proteins that are modified by S- nitrosylation in ALI and determine the effects of S-nitrosylation on their inflammatory activities.. Completion of these specific aims should provide a fuller understanding of SNO-regulated pathways in the airways and will guide the further study of SNO-based therapy for the prevention and resolution of inflammatory lung injury. PUBLIC HEALTH RELEVANCE: Ethyl nitrite (ENO), a gaseous S-nitrosylating agent, is protective in animal models of acute lung injury. We will determine the molecular targets of ENO therapy by quantifying gene and protein level changes, as well as protein S-nitrosylation, in the airways of ENO-treated mice

描述（由申请方提供）：急性肺损伤（ALI）/急性呼吸窘迫综合征（ARDS）的特征为初始气道炎症损伤，导致弥漫性肺泡损伤，随后发展为呼吸衰竭。尽管在美国发病率约为200，000例/年，死亡率接近40%，但尚无治疗ALI/ARDS的有效疗法。S-亚硝基硫醇（SNO）是内源性产生的一氧化氮的生物活性形式，其功能是抑制呼吸道上皮细胞中的免疫反应途径。最近，我们证明，气道SNO急性耗尽在小鼠模型的ALI和治疗吸入亚硝酸乙酯（ENO），S-亚硝基化剂，防止肺损伤的发展。然而，SNOs在肺气道中的分子靶点仍有待识别。我们假设，来自气道衬里液分析的蛋白质组特征可用于阐明ALI中SNO调节的免疫反应途径，这是ENO治疗的药理学基础。因此，我们建议：1.表征ENO治疗对ALI气道蛋白质组的影响，并鉴定受SNO补充影响的信号通路;和2.鉴定ALI中S-亚硝基化修饰的BALF蛋白，并确定S-亚硝基化对其炎症活性的影响。这些具体目标的完成应该提供气道中SNO调节途径的更全面的理解，并将指导基于SNO的治疗用于预防和解决炎性肺损伤的进一步研究。 公共卫生相关性：亚硝酸乙酯（ENO）是一种气态S-亚硝基化剂，在急性肺损伤动物模型中具有保护作用。我们将通过定量ENO治疗小鼠气道中基因和蛋白水平的变化以及蛋白S-亚硝基化来确定ENO治疗的分子靶点