S-nitrosothiols, NF-KappaB and Inflammation in Acute Lung Injury

S-亚硝基硫醇、NF-KappaB 与急性肺损伤中的炎症

• 批准号: 8759365
• 负责人: HARVEY E MARSHALL
• 金额: $ 39.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759365
• 关键词: Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Biological Markers; Blood; Breathing; Bronchoalveolar Lavage Fluid; Cells; Chemicals; Clinical; Cytokine Activation; DNA Binding; Data; Development; Disease; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Functional disorder; Gases; Genetic Transcription; Immune response; Impairment; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Knowledge; Lead; Liquid substance; Lung; Lung Inflammation; Lung diseases; Measures; Mediator of activation protein; Metabolism; Modeling; Modification; Mus; NF-kappa B; Nitric Oxide; Outcome; Oxygen; Pathogenesis; Pathway interactions; Patients; Peritoneal; Phase; Physiological; Pneumonia; Prevention; Preventive; Process; Property; Proteins; Public Health; Reactive Nitrogen Species; Research Project Grants; Role; S-Nitrosothiols; Sepsis; Severity of illness; Staging; Structure of parenchyma of lung; Structure of respiratory epithelium; Sulfhydryl Compounds; Supportive care; TNF gene; TNFRSF5 gene; Testing; Thioredoxin; Tissues; Transgenic Model; United States; airway inflammation; clinically significant; cohort; cytokine; effective therapy; ethyl nitrite; improved; inhibitor/antagonist; lung injury; mortality; mouse model; neutrophil; p65; prevent; public health relevance; research clinical testing; respiratory; response; therapy design; transcription factor

DESCRIPTION (provided by applicant): The pathogenic progression of acute lung injury (ALI) involves airway inflammation, epithelial injury, and the impairment of gas exchange. Despite concerted public health efforts, no effective therapy exists to prevent ALI and mortality remains >30%. S-nitrosothiols (SNOs) are endogenous molecules produced by the respiratory epithelium that are found in high concentration in the lung. SNOs serve an anti-inflammatory role by inhibiting activation of immune response pathways, including NF-kB. SNOs inhibit NF-kB by targeting the p65 subunit of the activating heterodimer (p50-p65) for S-nitrosylation. Using a mouse LPS model, we have shown that lung SNOs are depleted early in the course of ALI which occurs in conjunction with p65 denitrosylation, NF-kB activation, and airway inflammation. Augmenting lung SNOs prevents lung inflammation/injury by inhibiting NF-kB denitrosylation, emphasizing the pathophysiological importance of this mechanism. Recently, we have shown cytokines similarly induce p65 denitrosylation in the respiratory epithelium with this process regulated by thioredoxin (Trx). Trx inhibitors prevent p65 denitrosylation, NF-kB activation, and cytokine expression in the ALI model, suggesting Trx to be the mediator of SNO depletion. These data support our hypothesis that SNO depletion is a critical factor in ALI pathogenesis. To test this hypothesis, we formulated the following aims: 1. Determine if Trx regulates lung SNO metabolism and initiates the inflammatory response in ALI. 2. Determine if lung SNO augmentation inhibits the development of pneumonia- and sepsis-related ALI. 3. Quantify airway SNOs in ALI/ARDS patients and correlate with disease severity/outcomes. We anticipate that completion of the proposed aims will provide the translational data that is essential to support the clinical testing of airway SNO repletion as treatment for the prevention and development of ALI.

描述（由申请人提供）：急性肺损伤（ALI）的致病进展涉及气道炎症，上皮损伤和气体交换损害。尽管有一致的公共卫生工作，但仍未有有效的治疗方法可以防止ALI和死亡率保持> 30％。 S-亚硝基硫醇（SNO）是由肺部高浓度发现的呼吸上皮产生的内源分子。 SNO通过抑制包括NF-KB在内的免疫反应途径的激活来发挥抗炎作用。 SNO通过靶向激活异二聚体（P50-P65）的p65亚基来抑制NF-KB。使用小鼠LPS模型，我们表明肺SNO在ALI的早期耗尽，这与p65硝基化，NF-KB激活和气道炎症结合使用。通过抑制NF-KB脱硝基化，增强肺SNO可防止肺部炎症/损伤，强调该机制的病理生理重要性。最近，我们已经显示细胞因子类似地诱导呼吸性上皮中的p65硝基糖基化，该过程由硫氧还蛋白（TRX）调节。 TRX抑制剂可预防ALI模型中p65非硝基化，NF-KB激活和细胞因子表达，这表明TRX是SNO耗竭的介体。这些数据支持我们的假设，即SNO耗竭是ALI发病机理中的关键因素。为了检验这一假设，我们制定了以下目的：1。确定TRX是否调节肺SNO代谢并启动ALI中的炎症反应。 2。确定肺SNO增强是否抑制了与肺炎和败血症相关的ALI的发展。 3。量化ALI/ARDS患者的气道SNOS，并与疾病的严重程度/结局相关。我们预计，提出的目标的完成将提供转化数据，这对于支持气道SNO补充的临床测试作为预防和发展ALI的临床测试至关重要。