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：
7573772
负责人：
Sadis Matalon
金额：
$ 26.4万
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/7573772
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 Constriction procedure Cyclic AMP Data Deferoxamine Methanesulfonate Development Diagnosis Disease Edema Elderly Electrophysiology (science)Epithelial Epithelial Cells Epithelium Event 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 Physiological reperfusion Plasma Proteins Population Principal Investigator Production Proteins Pulmonary Edema Purpose 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 Stress Structure of parenchyma of lung System TRP channel Testing Therapeutic Therapeutic Agents Thinking Time Tissues Toxicology United States Food and Drug Administration Universities Vascular Diseases Ventilatory Depression Viral Load result Vulnerable Populations age group airway obstruction alveolar epithelium ascorbate base cytokine cytotoxicity day drug development improved in vivo indexing interest irritation lung injury member mortality novel pandemic influenza prevent programs receptor research study respiratory response sodium channel proteins sodium ion surfactant

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.

计划简介和目标声明根据RFA-NS-08-004中规定的说明，我们提交了一个研究中心卓越（RCE）的申请名为：“氯诱导心脏损伤的新型治疗方法呼吸系统”。卓越研究中心的主要目的是整合来自两个领先机构的高度产品调查员（阿拉巴马大学伯明翰和耶鲁大学大学）具有呼吸道生物学的潜水和免费专业知识，气道神经感控制功能，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。总体目标是测试新的治疗策略涉及FDA批准的代理商或当前正在接受临床试验的新型药物，当施用后暴露后能够逆转CI2引起的肺上皮和肺部的损伤，健康和患有肺部疾病的患者的全身血管。 RCE发芽在反战网络的第一次会议上并发现许多共同利益后，决定进行合作。我们同意有必要研究氯暴露对患有肺部疾病的动物的影响。我们决定集中于两种影响大量成年人和小儿种群的疾病：哮喘和呼吸综合病毒感染。以下第二个观察结果，由这个高度的成员进行综合团队构成了RCE拟议研究的合理基础。 »大鼠和小鼠以工业期间可能遇到的浓度暴露于CI2气体事故或化学战在肺上皮衬里中耗尽抗坏血酸和减少的谷胱甘肽流体渲染气道和肺泡上皮细胞对随后的氧化剂损伤无防御能力。这观察提供了使用抗坏血酸和N-乙酰半胱氨酸的理由（均为FDA批准用于人使用）作为CI2后暴露疗法。 �CI2刺激兴奋性气道神经元导致呼吸抑郁，支气管收缩，增加粘液生产和气道目标。在第二个实验中，乔德博士表明这些事件是通过激活离子通道TRPA1（瞬态受体）引发的电位Ankyrin 1）通过CI2衍生的反应性中间体。这些观察为提议使用TRPA1通道拮抗剂和抗氧化剂以停用TRPA1和其他TRP 通道因此限制CI2诱导肺损伤和气道刺激。 �CI2吸入损害肺泡上皮细胞，从而降低了其主动运输钠离子的能力并防止血浆蛋白进入肺泡空间。这导致蛋白质的形成丰富的肺泡水肿和呼吸衰竭。该观察为使用的合理依据短期和长期作用 /？2激动剂以及抗氧化剂，以激活肺泡流体清除率，并在同一时间反向气道收缩。研究人员在项目3中对研究人员进行的开创性观察表明，吸入氧化物气体不损害仅呼吸道和肺泡上皮，但也是肺和全身血管。这些事件是eNOS信号通路失活的结果，这可能导致血管疾病（例如动脉粥样硬化）的加速。这种观察为合理的基础设定了利用亚硝酸盐作为一氧化氮独立的eNOS来源，从而改善了血管张力和限制炎症和细胞毒性。确实，令人兴奋的协作产生的令人兴奋的初步数据 Patel博士和Matalon博士之间的努力，并在项目1和3中显示，提供了第一个证据，证明 CI2后硝酸盐管理（由FDA批准的人类使用的代理商）大幅下降 CI2诱导肺损伤。 »小鼠感染了呼吸道合胞病毒，该病毒感染了所有年龄段，特定的儿童和较早的儿童会减少Alloolar流体清除率，增加稳态肺中反应性物种的浓度，并引起轻度低氧血症和肺水肿。该观察结果以及文献研究表明动物和轻度肺的患者 PHS 398/2590（修订版09/04，重新发行4/2006）第102页延续格式页面首席调查员/计划总监（最后，第一，中间）：Matalod，Sadjs 疾病对随后的氧化应激高度敏感，强调了仔细的重要性记录脆弱人群如何应对CI2吸入。 �文献中的现有证据和乔德博士最近的观察结果，表明哮喘患者即使暴露于非常低（认为是无害的），也会产生严重的支气管收缩 CI2的浓度。乔德博士假设哮喘和现有的炎症反应 Senstitations对TRPA1通道进行了启用，增加了对随后的CI2暴露的反应。这些观察为测试用气道测试动物模型的响应的合理基础对CI2的高敏性。值得指出的是，RSV感染使儿童易于哮喘的发展。总结：（1）我们正在从两个现有的UO1延长以前的第二个观察结果（Jordt Dr. Jordt和 MATALON）评估脆弱人群中的CI2毒性；（2）我们招募了一个杰出但高度的年轻人有成熟的研究者已经对使用亚硝酸盐作为疗法进行了半观察纠正缺血重灌注的代理；（3）我们提议建立一个综合团由抗氧化剂组成的治疗剂；亚硝酸盐，TRP通道拮抗剂和02个激动剂在正常动物和患有肺部和全身系统的CI2治疗中，先前存在的肺部疾病。