Role of the endogenous gasotransmitter H2S in ETS-mediated airway disease

内源性气体递质 H2S 在 ETS 介导的气道疾病中的作用

• 批准号: 9272402
• 负责人: Roberto P Garofalo
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9272402
• 关键词: Acute; Affect; Age-Months; Air; Allergens; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Antiviral Response; Asthma; Breathing; Bronchiolitis; Case-Control Studies; Child; Childhood; Childhood Asthma; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Cigar; Cigarette; Clinic; Clinical; Clinical Research; Comorbidity; Complex; Complex Mixtures; Cotinine; Cystathionine; Cystathionine beta-Synthase; Cysteine Desulfhydrase; Cysteine Metabolism Pathway; Data; Defect; Developed Countries; Developing Countries; Development; Disease; Enrollment; Environmental Risk Factor; Environmental Tobacco Smoke; Enzyme-Linked Immunosorbent Assay; Enzymes; Epidemic; Epithelial Cells; Exhalation; Future; Gases; Gene Transfer; Hair; Health; Hospitalization; Hour; Hydrogen Sulfide; Immune System Diseases; Immune response; Inbred BALB C Mice; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Investigation; Laboratories; Life; Link; Lower Respiratory Tract Infection; Lung; Lung Inflammation; Lung diseases; Lyase; Mainstreaming; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Molecular; Morbidity - disease rate; Mucous Membrane; Mus; National Institute of Allergy and Infectious Disease; National Institute of Environmental Health Sciences; Neonatal; Outpatients; Oxidative Stress; Pathway interactions; Patients; Pediatric Hospitals; Production; Reagent; Resources; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Respiratory syncytial virus; Risk; Risk Factors; Role; Sampling; Seasons; Serum; Severities; Severity of illness; Side; Signal Transduction; Smoke; Smoker; Smoking; Stream; Structure of parenchyma of lung; Symptoms; Testing; Therapeutic; Tobacco smoke; Vascular Diseases; Viral; Viral Bronchiolitis; Viral Respiratory Tract Infection; Virus Replication; Water; Wheezing; adenoviral-mediated; airway hyperresponsiveness; airway inflammation; airway obstruction; allergic airway inflammation; antiviral immunity; base; environmental tobacco smoke exposure; epidemiology study; experience; high risk infant; infancy; innovation; middle childhood; mouse model; non-smoker; novel; overexpression; particle; pathogen; postnatal; public health relevance; recombinant adenovirus; research study; respiratory; respiratory virus; translational study; urgent care; Acute; Affect; Age-Months; Air; Allergens; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Antiviral Response; Asthma; Breathing; Bronchiolitis; Case-Control Studies; Child; Childhood; Childhood Asthma; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Cigar; Cigarette; Clinic; Clinical; Clinical Research; Comorbidity; Complex; Complex Mixtures; Cotinine; Cystathionine; Cystathionine beta-Synthase; Cysteine Desulfhydrase; Cysteine Metabolism Pathway; Data; Defect; Developed Countries; Developing Countries; Development; Disease; Enrollment; Environmental Risk Factor; Environmental Tobacco Smoke; Enzyme-Linked Immunosorbent Assay; Enzymes; Epidemic; Epithelial Cells; Exhalation; Future; Gases; Gene Transfer; Hair; Health; Hospitalization; Hour; Hydrogen Sulfide; Immune System Diseases; Immune response; Inbred BALB C Mice; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Investigation; Laboratories; Life; Link; Lower Respiratory Tract Infection; Lung; Lung Inflammation; Lung diseases; Lyase; Mainstreaming; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Molecular; Morbidity - disease rate; Mucous Membrane; Mus; National Institute of Allergy and Infectious Disease; National Institute of Environmental Health Sciences; Neonatal; Outpatients; Oxidative Stress; Pathway interactions; Patients; Pediatric Hospitals; Production; Reagent; Resources; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Respiratory syncytial virus; Risk; Risk Factors; Role; Sampling; Seasons; Serum; Severities; Severity of illness; Side; Signal Transduction; Smoke; Smoker; Smoking; Stream; Structure of parenchyma of lung; Symptoms; Testing; Therapeutic; Tobacco smoke; Vascular Diseases; Viral; Viral Bronchiolitis; Viral Respiratory Tract Infection; Virus Replication; Water; Wheezing; adenoviral-mediated; airway hyperresponsiveness; airway inflammation; airway obstruction; allergic airway inflammation; antiviral immunity; base; environmental tobacco smoke exposure; epidemiology study; experience; high risk infant; infancy; innovation; middle childhood; mouse model; non-smoker; novel; overexpression; particle; pathogen; postnatal; public health relevance; recombinant adenovirus; research study; respiratory; respiratory virus; translational study; urgent care

 DESCRIPTION (provided by applicant): Environmental tobacco smoke (ETS) is a complex mixture of gases and particles that include smoke from the burning cigarette, cigar, or pipe tip (side-stream smoke, SS) and exhaled mainstream smoke (MS). It is involuntarily inhaled by nonsmokers, lingers in the air for hours after cigarettes have been extinguished, and can induce or exacerbate a wide range of lung diseases, from cancer to respiratory infections, chronic obstructive pulmonary disease (COPD) and asthma (4;5). Exposure to ETS continues to be common despite a decline in smoking in developed countries and despite evidence of serious health effects. Respiratory syncytial virus (RSV) is the single most important viral pathogen causing acute lower respiratory-tract infections (bronchiolitis) in children and predisposing to th development of childhood asthma. Exposure to ETS is a known risk factor for the development of severe RSV infections, yet the mechanisms that determine ETS/RSV infection co-morbidity are largely unknown. Severity of bronchiolitis is driven by higher level of viral replication in th airways, as shown in studies of neonatal mice exposed to SHTS prior to RSV infection. Hydrogen sulfide (H2S) is a gasotransmitter which is endogenously generated from cysteine metabolism mainly by the activity of two enzymes, cystathionine gamma-lyase (CSE) and cystathionine-beta-synthase (CBS), with CSE being the main H2S-forming enzyme in lung tissue. Lower levels of H2S have been demonstrated in serum of smokers, and negatively correlate with the severity of airway obstruction in patients with COPD. Recent investigations in our laboratory have discovered a previously unrecognized function of H2S as antiviral mediator in airway epithelial cells and in the lung. We propose the hypothesis that exposure to ETS inhibits the expression of the endogenous H2S-generating enzyme CSE, causing a relative defect in H2S levels in the lung, resulting in enhanced viral replication. Two Aims will be pursued in this exploratory project. Aim 1 will test the hypothesis that the endogenous H2S-generating CSE enzyme is a critical determinant of severe bronchiolitis in children exposed to ETS. Specifically, we will test the primary hypothesis that expression of CSE is reduced in RSV- infected subjects who are exposed to ETS, resulting in lower H2S production, enhanced viral replication and greater severity of illness. In Aim 2 will test the hypothesis that CSE overexpression or direct H2S increased production in lungs of mice will blunt RSV replication and affect antiviral responses. To test this hypothesis, we will increase H2S production by CSE overexpression in the lung by replication deficient recombinant adenovirus-mediated gene transfer or by the use of GYY4137, a novel water-soluble H2S donor. Our experience with translational studies of RSV and ETS is ideal to pursue this innovative project. The results should have important therapeutic implications by identifying new strategies to treat primary respiratory viral infections or exacerbations of chronic underlying lung diseases that are associated with exposure to ETS.

 描述（由适用提供）：环境烟草烟雾（ET）是气体和颗粒的复杂混合物，包括燃烧的香烟，香烟或管道尖端（侧流烟雾，SS）和呼出的主流烟雾（MS）。它是由非吸烟者不由自主地掺入的，在烟雾爆发后，空气中徘徊了几个小时，并且可以诱导或加剧各种肺部疾病，从癌症到呼吸道感染，慢性阻塞性肺疾病（COPD）（COPD）（COPD）和ASTHMA（4; 5; 5）。尽管发达国家的吸烟减少并希望证据表现出严重的健康影响，但对ETS的接触仍然很普遍。呼吸道合胞病毒（RSV）是儿童急性下呼吸道感染（支气管炎）的最重要的唯一的病毒病原体，并且倾向于童年哮喘的发展。暴露于ETS是出现严重RSV感染的已知危险因素，但是确定ETS/RSV感染合并症的机制在很大程度上尚不清楚。如在RSV感染之前暴露于SHTS的新生小鼠的研究所示，气管炎的严重程度是由气道中较高的病毒复制驱动的。 Hydrogen sulfide (H2S) is a gasotransmitter which is endogenously generated from cysteine ​​metabolism mainly by the activity of two enzymes, cystathionine gamma-lyase (CSE) and cystathionine-beta-synthase (CBS), with CSE being the main H2S-forming enzyme in lung tissue.在吸烟者的血清中已经证明了H2的水平较低，并且与COPD患者的气道异议的严重程度呈负相关。我们实验室的最新研究发现了先前无法识别的H2s作为气道上皮细胞和肺中的抗病毒介质的功能。我们提出这样的假设，即暴露于ETS抑制内源性H2S生成酶CSE的表达，从而导致肺中H2S水平的相对缺陷，从而增强病毒复制。这个探索性项目将追求两个目标。 AIM 1将检验以下假设：内源性H2S生成CSE酶是暴露于ETS的儿童中严重细支气管炎的关键决定剂。具体而言，我们将测试主要假设，即暴露于ETS的RSV感染受试者中CSE的表达降低，导致H2S产生较低，病毒复制增强和疾病的严重程度更高。在AIM 2中，将检验以下假设：CSE过表达或直接H2S增加小鼠肺的产生将钝化RSV复制并影响抗病毒反应。为了检验这一假设，我们将通过复制不足的重组腺病毒介导的基因转移或使用GYY4137（一种新型的水溶性H2S供体）来增加肺中CSE过表达的H2S产生。我们在RSV和ETS转化研究方面的经验是追求这一创新项目的理想选择。结果应通过确定治疗与ETS暴露有关的慢性潜在肺部疾病的原发性呼吸道病毒感染或加剧的新策略，具有重要的治疗意义。