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

 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（由申请人提供）：环境烟草烟雾（ETS）是气体和颗粒的复杂混合物，包括燃烧的香烟、雪茄或烟斗尖端产生的烟雾（侧流烟雾，SS）和呼出的主流烟雾（MS）。它会被不吸烟者不自觉地吸入，香烟熄灭后会在空气中残留数小时，并可能诱发或加剧多种肺部疾病，从癌症到呼吸道感染、慢性阻塞性肺病。 (COPD) 和哮喘 (4;5)，尽管发达国家吸烟率有所下降，而且有证据表明呼吸道合胞病毒 (RSV) 是导致急性低血压的最重要的病毒病原体。儿童呼吸道感染（细支气管炎）和易患儿童哮喘 暴露于 ETS 是发生严重 RSV 感染的已知危险因素，但决定 ETS/RSV 感染的机制。毛细支气管炎的严重程度很大程度上是由气道中较高水平的病毒复制引起的，对 RSV 感染前暴露于 SHTS 的新生小鼠的研究表明，硫化氢 (H2S) 是一种内源性气体递质。半胱氨酸代谢主要通过两种酶的活性，胱硫醚γ-裂解酶（CSE）和胱硫醚-β-合酶（CBS）， CSE 是肺组织中主要的 H2S 形成酶，已证明吸烟者血清中的 H2S 水平较低，并且与 COPD 患者气道阻塞的严重程度呈负相关。 H2S 作为气道上皮细胞和肺部的抗病毒介质，我们提出这样的假设：暴露于 ETS 会抑制内源性 H2S 生成酶 CSE 的表达，从而导致相对缺陷。该探索性项目将追求两个目标：生成 H2S 的 CSE 酶是接触 ETS 的儿童发生严重细支气管炎的关键决定因素。 ，我们将测试主要假设，即暴露于 ETS 的 RSV 感染受试者中 CSE 表达减少，导致 H2S 产生减少、病毒复制增强和疾病严重程度增加。图2将检验以下假设：CSE过度表达或直接增加小鼠肺部的H2S产量将削弱RSV复制并影响抗病毒反应。为了检验这一假设，我们将通过复制缺陷重组腺病毒介导的基因通过CSE过度表达来增加肺部的H2S产量。转移或使用 GYY4137（一种新型水溶性 H2S 供体），我们在 RSV 和 ETS 转化研究方面的经验是开展这一创新项目的理想选择。通过确定治疗原发性呼吸道病毒感染或与接触 ETS 相关的慢性潜在肺部疾病恶化的新策略来获得治疗意义。