Mech of Brevetoxin- Induced Bronchial & Nasal Resp in Allergic & Non-Allergic

短尾毒素诱导支气管的机械作用

• 批准号: 7645751
• 负责人: William Abraham
• 金额: $ 21.66万
• 依托单位: UNIVERSITY OF NORTH CAROLINA WILMINGTON
• 依托单位国家: 美国
• 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/7645751
• 关键词: Acute; Address; Adverse event; Affect; Airway Resistance; Allergic; Breathing; Bronchoconstriction; Cell Adhesion Molecules; Cell physiology; Cells; Chemical Structure; Chemicals; Cholinergic Agents; Complex; Data; Dinophyceae; Disease; Employee Strikes; End Point; Environment; Environmental Health; Environmental Risk Factor; Event; Exposure to; Florida; Generations; Grant; Host Defense Mechanism; Human; IL8 gene; Immunosuppression; Individual; Inflammation; Inflammatory; Intervention; Irrigation; Link; Lung; Measurement; Measures; Mental Depression; Modeling; Modification; Mucociliary Clearance; Mucous body substance; NF-kappa B; Neutrophil Infiltration; Nose; Parents; Pharmacology; Physiological; Poison; Population; Positioning Attribute; Progress Reports; Receptor Cell; Regulation; Research Personnel; Resistance; Role; Severities; Sheep; Site; Source; Structure; Study models; Symptoms; Tail; Testing; Toxic effect; Toxin; Work; aerosolized; airway hyperresponsiveness; airway inflammation; analog; brevetoxin; cholinergic; concept; cytokine; day; experience; field study; functional group; improved; in vivo; macrophage; novel; programs; pulmonary function; receptor; red tide; research study; respiratory; response

During red tide events aerosolized polyether brevetoxins (PbTxs) have been linked to upper and lower airway symptoms in both normal individuals and in "susceptible populations", i.e. those individuals with pre-existing airway disease. During the first grant cycle we showed that sheep inhaling PbTxs environmentally relevant concentrations of PbTx developed adverse pulmonary events including acute bronchoconstriction, airway hyperresponsiveness (AHR), airway inflammation and decreased mucociliary clearance. Both normal and allergic sheep, which serve as a surrogate for a "susceptible population", responded to toxin challenge, but the severity of the response was, in part, dependent on the underlying inflammatory status of the airways. The most striking findings, however, were that the airway effects of the inhaled PbTxs differed in their physiological actions and their response to pharmacologic intervention. The differences in responses were related to changes in the chemical structure of the PbTx tested. To further complicate the problem, we found that a natural congener of PbTx and chemically modified PbTxs not only could block the adverse pulmonary effects of PbTx, but in some instances, improve pulmonary function on their own. These findings suggest that synthetic and/or natural modifications of the PbTx molecules can result in the generation of compounds that have increased toxicity, or depending on the structural modification, beneficial effects in the airway. Therefore, in this proposal we will test the hypothesis that the severity of the airway effects of inhaled toxins, i.e. effects on bronchial tone, airway responsiveness, mucociliary clearance, inflammatory cell recruitment and airway cell function are dependent on the chemical structure(s) of the individual PbTxs that are aerosolized. Furthermore, we postulate that the PbTx congeners and analogs can stimulate different pulmonary cells/receptors and that the PbTx-induced effects (whether beneficial or harmful) will be dependent on cells/receptors on various pulmonary cells stimulated by the toxins. Three Specific Aims will be used to test this hypothesis. Specific Aim 1: A) To compare the effects of selected PbTxs (both natural and synthetic toxins), PbTx congeners and toxin complexes identified in field studies on measures of bronchial tone (pulmonary airflow resistance, RL) and mucociliary clearance (tracheal mucus velocity, TMV and whole lung mucociliary clearance, MCC) to identify the chemical structure(s) responsible for the observed effects whether beneficial or harmful. And B) To use in vivo pharmacology to identify airway cells/receptors responsible for toxin-induced effects. Specific Aim 2: To determine the mechanisms responsible for the airway inflammation and airway hyperresponsiveness (AHR) that result from 4-day PbTx exposure, including the regulation of nuclear factor kappa beta (NFkB) activation, subsequent cytokine release and the role of adhesion molecule activation. Specific Aim 3: To determine if the immunosuppressive effects of PbTx on macrophages and the PbTx-induced depressions in TMV seen after toxin exposures affect bacterial clearance in vivo. We will continue to utilize the sheep model for these studies because this model responds to inhaled concentrations of toxin that are present in the environment and cause respiratory symptoms in humans and comparisons between normal and allergic sheep allow us to model airway effects in "normal" and "susceptible populations". Furthermore, as demonstrated in the Progress Report / Preliminary Studies, the physiologic endpoints measured in this model have adequate sensitivity to differentiate amongst the PbTx congeners that differ by a single atom or functional group, thereby providing confidence that the proposed Specific Aims can be accomplished. The data generated in this proposal are novel in that they provide an approach to understanding how structure and composition of aerosolized toxin affects the airways. The experiments are being conducted at environmentally relevant concentrations. Because of our extensive experience with delineating inflammatory cascades in this model, we are well positioned to understand mechanisms involved in toxin-induced inflammation in the airways and the potential of toxin exposure to impair host defense mechanisms. With the current paucity of data addressing these issues, the proposed studies should provide needed information on the pathophysiological consequences of PbTx exposure.

在红潮发生期间，雾化的聚醚Brevetoxins（PBTX）已与上部联系起来 正常人和“易感人群”中的气道症状降低，即 预先存在的气道疾病。在第一个赠款周期中，我们表明绵羊在环境上吸入PBTXS 相关浓度PBTX开发了不良肺部事件，包括急性支气管收缩， 气道高反应性（AHR），气道炎症和粘膜纤毛清除率降低。两者都正常 对“易感人群”的替代物的过敏绵羊对毒素挑战做出了回应，但 反应的严重程度部分取决于气道的潜在炎症状态。这 然而，最引人注目的发现是吸入PBTX的气道影响在其生理上有所不同 行动及其对药理干预的反应。响应的差异与 测试的PBTX化学结构的变化。为了进一步使问题复杂化，我们发现 PBTX和化学修饰的PBTX的天然同源物不仅可以阻止肺部不良影响 pbtx的作用，但在某些情况下，会自行改善肺功能。这些发现表明 PBTX分子的合成和/或自然修饰会导致产生的化合物 毒性增加，或者取决于结构修饰，在气道中有益效果。所以， 在该提案中，我们将检验以下假设：吸入毒素的气道影响的严重程度，即 对支气管张力，气道反应能力，粘膜校正清除，炎症细胞募集的影响 气道细胞功能取决于单个PBTX的化学结构 雾化。此外，我们假设PBTX同类物和类似物可以刺激不同的 肺部细胞/受体以及PBTX诱导的作用（有益还是有害）将取决于 毒素刺激的各种肺细胞上的细胞/受体上。三个具体目标将用于 检验此假设。特定目的1：a）比较选定的PBTX的效果（自然和合成 毒素），PBTX同类物和毒素复合物在现场研究中鉴定出支气管张力的度量 （肺动气流耐药性，RL）和粘膜缩减清除率（气管粘液速度，TMV和整个肺 MCC）的粘膜纤毛清除率），以确定负责观察到的影响的化学结构是否存在 有益或有害。 b）使用体内药理学来识别负责的气道细胞/受体 毒素诱导的作用。特定目的2：确定导致气道炎症的机制 由4天PBTX暴露引起的气道高反应性（AHR），包括调节 核因子Kappaβ（NFKB）激活，随后的细胞因子释放和粘附分子的作用 激活。特定目的3：确定PBTX对巨噬细胞和 PBTX诱导的毒素暴露后观察到的TMV下降会影响体内细菌清除率。我们将 继续利用这些研究的绵羊模型，因为该模型对吸入浓度的反应 在环境中存在的毒素并引起人类的呼吸症状和比较 在正常和过敏性绵羊之间，我们可以在“正常”和“易感人群”中对气道效应进行建模。 此外，正如进度报告 /初步研究所证明的那样，生理终点 在此模型中测得的敏感性足以使PBTX同类物之间的区分，而这些pbtx同类员因a而不同 单个原子或功能群体，从而提供了信心，表明拟议的特定目的可以是 成就。本提案中产生的数据是新颖的，因为它们提供了一种理解的方法 雾化毒素的结构和组成如何影响气道。实验正在进行 在环境相关的浓度下。因为我们在描述炎症方面的丰富经验 在此模型中，我们有能力理解毒素诱导的机制 气道的炎症以及毒素暴露于损害宿主防御机制的潜力。与 当前缺乏解决这些问题的数据，拟议的研究应提供所需的信息 PBTX暴露的病理生理后果。