RSV infections augment Cl2 induced injury to the respiratory system

RSV 感染会加剧 Cl2 引起的呼吸系统损伤

基本信息

批准号：
7857980
负责人：
Sadis Matalon
金额：
$ 27万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7857980
关键词：
Acceleration Acetylcysteine Adrenergic Agonists Adult Aerosols Affect Agonist Alabama Alveolar Animal Model Animals Ankyrins Anti-Inflammatory Agents Anti-inflammatory Antioxidants Asthma Atherosclerosis Biochemistry Biology Blood Vessels Breathing Bronchoconstriction CCL4 gene Cells Centers of Research Excellence Chemical Warfare Child Childhood Chlorine Clinical Trials Communities Cyclic AMP Data Deferoxamine Methanesulfonate Development Diagnosis Disease Edema Elderly Electrophysiology (science)Epithelial Epithelial Cells Epithelium Event FDA approved Free Radicals Gases Glutathione Disulfide Goals Human Hypersensitivity Hypoxemia In Vitro Inbred BALB C Mice Individual Industrial Accidents Infant Infection Inflammation Inflammatory Response Injection of therapeutic agent Injury Institution Instruction Ion Channel Ischemia Lead Liquid substance Literature Lower Respiratory Tract Infection Lung Lung diseases Measurement Measures Morbidity - disease rate Mucous body substance Mus Neurons Nitric Oxide Nitrites Oxidants Oxygen Patients Peritoneal Pharmaceutical Preparations Physics Plasma Proteins Population Principal Investigator Production Proteins Pulmonary Edema Rattus Recruitment Activity Reduced Glutathione Reperfusion Therapy Research Research Personnel Resistance Respiratory Failure Respiratory Syncytial Virus Infections Respiratory System Respiratory syncytial virus Seminal Series Signal Pathway Sodium Source Structure of parenchyma of lung System TRP channel Testing Therapeutic Therapeutic Agents Time Tissues Toxicology Universities Vascular Diseases Ventilatory Depression Viral Load result Vulnerable Populations age group airway obstruction alveolar epithelium ascorbate base constriction cytokine cytotoxicity drug development efficacy testing improved in vivo indexing interest irritation lung injury meetings member mortality novel oxidant stress pandemic influenza prevent programs receptor research study respiratory response sodium channel proteins sodium ion surfactant treatment strategy

项目摘要

Program Introduction and Statement of Objectives In accordance with the instructions set forth in RFA-NS-08-004, we are submitting a Research Center of Excellence (RCE) application entitled: "Novel Treatments of Chlorine Induced Injury to the Cardio- Respiratory Systems". The main purpose of this Research Center of Excellence is to integrate the efforts of highly productive investigators from two leading institutions (University of Alabama at Birmingham and Yale University) with diverse and complimentary expertise on airway biology, neurosensory control of airway function, environmental pulmonary toxicology, free radical biochemistry, ion channel electrophysiology, vascular biology, aerosol physics, and drug development. The overall goal is to test new treatment strategies involving FDA approved agents or newly developed drugs currently undergoing clinical trials, which when administered post exposure are capable of reversing CI2 induced injury to lung epithelia and pulmonary and systemic vasculatures in both healthy and individuals with pre-existing lung diseases. The RCE germinated during the first meeting of the CounterAct Network when Dr. Matalon and Jordt met, discussed their research, and upon discovering many common interests, decided to collaborate. We agreed that there was a need to investigate the effects of chlorine exposure on animals with pre-existing lung diseases. We decided to concentrate on two diseases affecting large fractions of the adult and pediatric populations: Asthma and Respiratory Syncytial Virus Infections. The following seminal observations, made by members of this highly integrated team, formed the rational basis for proposed research in the RCE. ¿ Exposure of rats and mice to CI2 gas in concentrations likely to be encountered during industrial accidents or chemical warfare depletes ascorbate and reduced glutathione in the lung epithelial lining fluid rendering airway and alveolar epithelial cells defenseless to a subsequent oxidant insult. This observation provides the rationale for the use of ascorbate and N-acetylcysteine (both FDA approved for human use) as post CI2 exposure therapeutics. ¿ CI2 stimulates excitatory airway neurons leading to respiratory depression, broncho-constriction, increased mucous production and airway obstruction. In a seminal series of experiments, Dr. Jordt showed that these events are initiated by activation of ion channel TRPA1 (Transient Receptor Potential Ankyrin 1) by CI2 derived reactive intermediates. These observations provide the basis for the proposed use of TRPA1 channel antagonists and antioxidants to deactivate TRPA1 and other TRP channels thus limiting CI2 induced lung injury and airway irritation. ¿ CI2 inhalation damages alveolar epithelial cells decreasing their ability to actively transport sodium ions and prevent the entry of plasma proteins in the alveolar space. This results in the formation of protein rich alveolar edema and respiratory failure. This observation provides the rational basis for the use of short and long term acting /?2 agonists along with antioxidants to activate alveolar fluid clearance and at the same time reverse airway constriction. ¿ Seminal observations by investigators in Project 3 show that inhalation of oxidant gases damages not only respiratory and alveolar epithelial but the pulmonary and systemic vasculatures as well. These events are the consequence of inactivation of the eNOS signaling pathway which may lead to acceleration of vascular diseases such as atherosclerosis. This observation sets the rational basis for the use of nitrite as an eNOS independent source of nitric oxide, thus improving vascular tone and limiting inflammation and cytotoxicity. Indeed, exciting preliminary data generated by collaborative efforts between Dr. Patel and Matalon, and shown in Projects 1 and 3, provide the first evidence that post CI2-administration of nitrite, an agent approved by the FDA for human use, significantly decreases CI2 induced lung injury. ¿ Infections of mice with Respiratory Syncytial Virus, an agent which infects all age groups and in particular children and the elderly, decreases alveolar fluid clearance, increases steady state concentrations of reactive species in the lungs, and causes mild hypoxemia and pulmonary edema. This observation, along with studies in the literature, showing that animals and patients with mild lung PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 102 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): MatalOD, SadJS disease are highly sensitive to subsequent oxidant stress, highlights the importance of carefully documenting how vulnerable populations respond to CI2 inhalation. ¿ Existing evidence in the literature and Dr. Jordt's recent observations, indicate that patients with asthma develop severe bronchoconstriction even when exposed to very low (thought to be innocuous) concentrations of CI2. Dr. Jordt hypothesizes that asthma and the existing inflammatory response senstitizes TRPA1 channels, increasing their responses to a subsequent CI2 exposure. These observations provide the rational basis for testing the response of animal models with airway hypersensitivity to CI2. It is worthwhile to point out that RSV infections predispose children to the development of asthma. In summary: (1) we are extending previous seminal observations from two existing UO1s (Drs. Jordt and Matalon) to assess CI2toxicity in vulnerable populations; (2) we have recruited an outstanding young but highly accomplished investigator who already has made seminal observations on the use of nitrite as a therapeutic agent in correcting ischemia-reperfusion; (3) we are proposing to establish an integrated regiment of therapeutic agents consisting of antioxidants; nitrite, TRP Channel antagonists and 02 agonists for the treatment of CI2 induced injury to the pulmonary and systemic systems in both normal animals and those with pre-existing lung disease.

计划简介和目标陈述根据 RFA-NS-08-004 中规定的说明，我们正在提交一个研究中心卓越（RCE）申请，标题为：“氯诱发心脏损伤的新型治疗方法” 呼吸系统”。这个卓越研究中心的主要目的是整合来自两个领先机构（阿拉巴马大学伯明翰分校和耶鲁大学）的高产研究人员大学）在气道生物学、气道神经感觉控制方面拥有多样化和互补的专业知识功能、环境肺毒理学、自由基生物化学、离子通道电生理学、血管生物学、气溶胶物理学和药物开发的总体目标是测试新的治疗策略。 FDA 涉及已批准的药物或目前正在进行临床试验的新开发药物，当暴露后给予的药物能够逆转 CI2 引起的肺上皮和肺和肺损伤。 RCE 在健康人和患有肺部疾病的个体中萌芽。在 CounterAct 网络第一次会议期间，Matalon 博士和 Jordt 会面，讨论了他们的研究，在发现许多共同利益后，我们一致认为有必要进行合作。研究氯暴露对已有肺部疾病的动物的影响。专注于影响大部分成人和儿童群体的两种疾病：哮喘和呼吸道合胞病毒感染以下是由该高度成员做出的开创性观察。综合团队，形成了 RCE 拟议研究的合理基础。 ¿大鼠和小鼠暴露于工业过程中可能遇到的浓度的 CI2 气体事故或化学战会消耗肺上皮层中的抗坏血酸和还原型谷胱甘肽液体使气道和肺泡上皮细胞对随后的氧化损伤失去防御能力。观察结果为使用抗坏血酸和 N-乙酰半胱氨酸（两者均获得 FDA 批准）提供了依据供人类使用）作为 CI2 暴露后治疗。 ¿ CI2 刺激兴奋性气道神经元，导致呼吸抑制、支气管收缩、乔特博士在一系列开创性的实验中发现，粘液分泌增多，气道阻塞。表明这些事件是由离子通道 TRPA1（瞬时受体潜在的锚蛋白1)由CI2衍生的反应中间体这些观察结果提供了基础。提议使用 TRPA1 通道拮抗剂和抗氧化剂来灭活 TRPA1 和其他 TRP 通道，从而限制 CI2 引起的肺损伤和气道刺激。 ¿ CI2 吸入会损害肺泡上皮细胞，降低其主动转运钠离子的能力并阻止血浆蛋白进入肺泡腔，从而导致蛋白质的形成。这一观察结果为肺泡水肿和呼吸衰竭的使用提供了合理依据。短期和长期作用的β2激动剂与抗氧化剂一起激活肺泡液清除和同时逆转气道收缩。 ¿项目3研究人员的研讨会观察表明，吸入氧化剂气体不会造成损害仅呼吸和肺泡上皮，但肺和全身脉管系统也是如此。事件是 eNOS 信号通路失活的结果，这可能导致这一观察结果为动脉粥样硬化等血管疾病的加速发展奠定了合理的基础。使用亚硝酸盐作为独立于 eNOS 的一氧化氮来源，从而改善血管张力和事实上，合作产生的令人兴奋的初步数据。 Patel 博士和 Matalon 之间的努力（如项目 1 和 3 所示）提供了第一个证据： CI2 施用亚硝酸盐（FDA 批准用于人类使用的药剂）后，显着降低 CI2诱发肺损伤。 ¿小鼠感染呼吸道合胞病毒，这种病毒可感染所有年龄组和人群特别是儿童和老年人，降低肺泡液清除率，增加稳态肺部反应性物质的浓度，并导致轻度低氧血症和肺水肿。这一观察结果与文献研究一起表明，患有轻度肺部疾病的动物和患者 PHS 398/2590（修订版 09/04，重新发布 4/2006）第 102 页延续格式页首席研究员/项目总监（最后、第一、中间）：MatalOD、SadJS 疾病对随后的氧化应激高度敏感，强调了仔细治疗的重要性记录弱势群体对 CI2 吸入的反应。 ¿文献中的现有证据和 Jordt 博士最近的观察表明，哮喘患者即使暴露在非常低的浓度（被认为是无害的）下，也会出现严重的支气管收缩 CI2 博士欺负哮喘和现有的炎症反应。使 TRPA1 通道变得敏感，增强其对后续 CI2 暴露的反应。观察结果为测试气道动物模型的反应提供了合理的基础对 CI2 过敏值得指出的是，RSV 感染使儿童易患 CI2。哮喘的发展。总之：（1）我们正在扩展之前对两个现有 UO1（Jordt 博士和 Matalon）评估高度脆弱人群的 CI2 毒性；（2）我们招募了一位优秀的年轻但成就卓著的研究人员，已经对亚硝酸盐作为治疗剂的使用做出了开创性的观察（三）建议组建一个综合团由抗氧化剂、TRP通道拮抗剂和02激动剂组成的治疗剂；治疗 CI2 对正常动物和患有此病的动物的肺部和全身系统造成的损伤预先存在的肺部疾病。