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: 7779980
• 负责人: HARVEY E MARSHALL
• 金额: $ 39万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7779980
• 关键词: Acute; Acute Lung Injury; Adaptor Signaling Protein; Address; Adult Respiratory Distress Syndrome; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Attenuated; Breathing; Bronchopulmonary Dysplasia; Cells; Complex; DNA Binding; Data; Development; Disease; Dose; Enzymes; Evolution; Functional disorder; Gases; Genetic; Harvest; Homeostasis; Immune response; In Vitro; 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; Molecular; Mus; NF-kappa B; NOS2A gene; NOS3 gene; Nitric Oxide; Nitric Oxide Synthase; Oxidoreductase; Oxygen; Pathway interactions; Phosphotransferases; Play; Pneumonia; Population; Post-Translational Protein Processing; Prevention; Production; Proteins; Rattus; Reaction; Reactive Oxygen Species; Regulation; Research Proposals; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Structure of parenchyma of lung; Sulfhydryl Compounds; Supportive care; TLR4 gene; TNFRSF5 gene; Testing; Therapeutic; Translating; United States; Wild Type Mouse; aerosolized; airway epithelium; airway inflammation; base; chemical property; clinically significant; cytokine; ethyl nitrite; extracellular; human NOS2A protein; inhaled nitric oxide; lung injury; macrophage; mortality; nitration; novel therapeutics; p65; public health relevance; response; transcription factor; treatment effect

DESCRIPTION (provided by applicant): S-nitrosothiols (SNO) are stable, bioactive nitric oxide (NO) compounds found at high concentration in the lung. By inhibiting activation of the transcription factor NF-(B, SNO alters the immune response with evidence suggesting that fluctuation in airway SNO levels serves to regulate pulmonary inflammation. S-nitrosoglutathione reductase (GSNOR) and nitric oxide synthase (NOS) are enzymes that control lung SNO concentrations by increasing SNO metabolism and production respectively. In this regard, LPS-induced NF-(B activity and airway inflammation is augmented in the lungs of inducible NOS (NOS2)-null (KO) mice and diminished in the lungs of GSNOR KO mice. Furthermore, lung SNO repletion by ethyl nitrite (ENO) gas inhibits LPS-induced NF-(B activity and inflammation. Given these observations, we hypothesize that SNO serves to attenuate lung inflammation by inhibiting activity in the NF-(B pathway. To test this hypothesis, we have formulated the following specific aims: 1. Determine the importance of SNO metabolism in the regulation of lung inflammation. 2. Determine the role of SNO in modulating NF-(B signaling in the lung. 3. Investigate the effect of lung SNO repletion on lung inflammation and NF-(B activity. The pulmonary inflammatory response of C57BL6 wild-type (WT), NOS2 KO, NOS3 KO and GSNOR KO mice to aerosolized LPS will be contrasted. SNO levels (in the lung and airway fluid) will be quantified and correlated to pathological determinants of lung inflammation and NF-(B activity. The specific step(s) in the NF-(B signal transduction pathway that are sensitive to SNO will be identified and the proteins that regulate these steps analyzed for post-translational modification by S-nitrosylation. The effect of treatment with inhaled ENO and conventional NO gas on these parameters in LPS-exposed WT mice will also be examined. Accomplishing these aims will delineate the importance of SNO metabolism in the evolution of inflammation in response to lung injury and further elucidate the molecular mechanism(s) by which SNO modulates the immune response. These data could then translate into new therapeutic strategies in the treatment of acute lung injury. PUBLIC HEALTH RELEVANCE: Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a disease with an annual incidence in the United States of approximately 190,000 cases and a mortality rate between 40-50%. Despite its clinical significance, the pathophysiology of ALI/ARDS remains poorly understood with treatment limited to supportive care. This research proposal will address the importance of endogenously-produced molecules termed S-nitrosothiols, in controlling the inflammation that is associated with ALI/ARDS. The knowledge gained from the proposed studies could lead to the development of new therapies that target inflammation in ALI/ARDS and other pulmonary disorders..

描述（由申请人提供）：S-硝基硫醇（SNO）是稳定的，生物活性一氧化氮（NO）化合物，在肺中高浓度下发现。通过抑制转录因子NF-的激活（B，SNO通过证据改变了免疫反应，表明气道SNO水平的波动可用于调节肺部炎症。S-硝基谷氨酸还原酶（GSNOR）（GSNOR）（GSNOR）和硝酸氧化物合成酶（NOS）是Lung SNO的浓度，而SNO的浓度是增加的。 LPS诱导的NF-（B活性和气道炎症在诱导NOS（NOS2） - null（KO）小鼠的肺中增加，并在GSNOR KO小鼠的肺中减少。此外，肺nitrite（ENO）的肺（ENO）气体抑制了LPS-lps-lps-lps-lps-lps-lps-lps-lps-lps-lps-lps-lps-lps-nf-（b）的活性NF-（B）肺Sno repletion和BINF-lps-lps-nf-（B）（B）（B）（B）（B）（B）（B）（BINDINID NF）。假设SNO通过抑制NF-的活性来减轻肺部炎症（B途径。为了检验该假设，我们已经提出了以下具体目的：1。确定SNO代谢在肺部炎症调节中的重要性。2。确定SNO在调节Nf-（b-lung lung nf-lung in Signal nf-nf-nf-nf）中的作用。 3。研究肺SNO诚意对肺部炎症和NF-的影响（B活性。C57BL6野生型（WT），NOS2 KO，NOS3 KO，NOS3 KO和GSNOR KO小鼠对肺动脉溶液的肺部炎症反应（NOS2 KO，NOS3 KO和GSNOR KO小鼠对肺部和空气级别的频率）。和NF-（B活性。NF-（B信号转导途径对SNO敏感的特定步骤）以及对这些步骤进行调节的蛋白质，通过S-硝基化进行了分析的这些步骤，以通过S-硝基化进行了翻译后修饰。通过对这些参数的影响，对这些参数的效果也将在LPS上验证，这些参数也将在这些范围内进行验证。 SNO代谢在对肺损伤的反应中的进化中的重要性，并进一步阐明了SNO调节免疫反应的分子机制。公共卫生相关性：急性肺损伤（ALI）或急性呼吸窘迫综合征（ARDS）是一种疾病，在美国，每年发病率约为190,000例，死亡率在40-50％之间。尽管具有临床意义，但ALI/ARDS的病理生理学仍然很少了解支持护理。这项研究建议将解决被称为S-硝基硫醇的内生产生的分子的重要性，在控制与ALI/ARDS相关的炎症中。从拟议的研究中获得的知识可能导致靶向ALI/ARD和其他肺部疾病的新疗法的发展。