Novel Treatments of Chlorine Induced Injury to the Cardio-Respiratory Systems-U54

描述(由申请人提供)： 该卓越研究中心(RCE)题为“氯对心脏呼吸系统损伤的新治疗方法”，由三个项目和两个核心组成。贯穿所有项目的统一主题是，动物暴露于C12会导致活性中间体的形成，这些中间体耗尽肺上皮液中的抗坏血酸和还原型谷胱甘肽，损害呼吸和肺泡上皮的关键成分[如瞬时受体蛋白(Trp)和上皮钠通道(ENaC)]，然后通过抑制eNOS信号损害肺和全身血管的精液功能。此外，我们建议在感染呼吸道合胞病毒或用卵白蛋白攻击的动物中，C12的这些毒性作用将会增强。在我们的第一系列实验中，我们将对RSV感染和卵白蛋白攻击的小鼠以及正常大鼠在接触C12之前和之后进行一些最先进的生化、生物物理、生理和形态测量，以记录肺上皮和肺和全身血管系统损伤的发生和发展。然后，我们将用抗氧化剂、色氨酸受体拮抗剂、/32激动剂和亚硝酸盐在C12暴露后以不同的间隔给药，无论是气管内还是通过雾化或腹膜内(抗氧化剂和亚硝酸盐)，并通过特定的功能测量来量化恢复。RCE的优势包括调查人员的多样化人才，独特的设施，以及初步数据的新颖性。这三个项目(其中两个建立在现有UO1赠款产生的新发现的基础上)得到了行政核心和暴露核心的支持，这两个核心发挥了关键作用，既提供了基本职能(如让动物接触C12)，又帮助将团队整合为一个有凝聚力的实体。

DESCRIPTION (provided by applicant): This Research Center of Excellence (RCE) entitled: "Novel Treatments of Chlorine Induced Injury to the Cardio-Respiratory Systems" consists of three projects and two cores. The unifying theme spanning all projects is that exposure of animals to C12 results in the formation of reactive intermediates which deplete ascorbate and reduced glutathione in the lung epithelial fluids, damage key components of the respiratory and alveolar epithelial [such as transient receptor protein (TRP) and epithelial sodium channels (ENaC)] and then, via inhibition of eNOS signaling compromise seminal functions of the pulmonary and systemic vasculatures. Furthermore, we propose that these toxic effects of C12 will be heightened in animals infected with respiratory syncytial virus or challenged with ova albumin. In our first series of experiments we will perform a number of state of the art biochemical, biophysical, physiological and morphometric measurements in RSV infected and ova albumin challenged mice as well as normal rats prior to and following C12 exposure to document the onset and progression of injury to lung epithelia and pulmonary and systemic vasculature. We will then treat them with antioxidants, TRP antagonists, /32 agonists and nitrite administered at various intervals post C12 exposure either intra-tracheally or via aerosolization or intraperitoneally (antioxidants and nitrite) and quantify recovery by specific functional measurements. Strong points of the RCE include the diverse talents of the investigators, the unique facilities, and the novelty of the preliminary data. The three projects (two of which build on novel findings generated by existing UO1 grants) are supported by an administrative core and the exposure core, which play key roles by both providing essential functions (such as exposure of animals to C12) and helping to integrate the team into a cohesive entity.