Mechanisms of brevetoxin induced bronchial & nasal response in airways

短尾毒素诱发支气管炎的机制

• 批准号: 6361820
• 负责人: William Abraham
• 金额: $ 17.91万
• 依托单位: UNIVERSITY OF NORTH CAROLINA WILMINGTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-10 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6361820
• 关键词: acetylcholine; bronchospasm; chemical kinetics; environmental health; laboratory mouse; laboratory rat; marine toxins; mast cell; norepinephrine; pathologic process; respiratory airway clearance; respiratory disorder; respiratory function; sheep

Project 3: Mechanisms of Brevetoxin Induced Bronchial and Nasal Response in Allergic and Non-Allergic Airways (Abraham) Description (Taken from the Investigator's Abstract) Inhalation of Florida "red tide" toxins has been associated with both lower and upper airway symptoms in humans such as non-productive cough, shortness of breath, rhinorrhea, and sneezing, and it has been suggested that the toxin predisposes asthma patients to exacerbations of the disease. Although previous studies suggest that the respiratory effects of the toxin are neurally mediated, the investigators' recent (preliminary) studies indicate that these adverse events involve not only a neuronal component, but a non-neuronal (mas cell) mediated component. Therefore, in the proposed project, the investigators will test the hypotheses that: 1) inhaled toxin contracts airway smooth muscle and airway vascular smooth muscle by releasing acetylcholine from cholinergic and norepinephrine from adrenergic neurons thereby activating muscarinic and alpha-adrenergic receptors in the airway, and that toxin-induced mast cell secretion of mediators with smooth muscle effects contributes to the neurally mediated effects, and 2) toxin induced-airway (both upper and lower) responses are potentiated in animals (sheep) with allergic inflammation as "models" of human asthma and allergic rhinitis. These hypothesis will be tested with the following specific aims: 1a) to compare the effect of inhaled of inhaled toxin on bronchial airway smooth muscle (bronchoconstriction and airway hyperreponsiveness), mucocilliary clearance (bronchoconstriction and airway hyperreponsiveness), mucocilliary clearance, and airway vascular smooth muscle tone (bronchial blood flow) in vivo, in sheep with and without allergic airway inflammation, 1b) to assess modification of the bronchoconstrictor, mucocilliary transport and vascular responses by model drugs that interfere with the proposed mechanisms of toxin action, and 1c) to evaluate the possibility that standard bronchodilators prevent or attenuate the responses to airborne toxin; 2) to compare the effect of nasally of nasally administered toxin on nasal airway resistance in allergic and non- allergic sheep, to assess modifications of the nasal responses by model drugs that interfere with the proposed mechanisms of toxin action and to evaluate the possibility that standard therapies prevent or attenuate the responses to toxin; 3) to determine the mechanism of toxin-induced mast cell activation using bronchoprovocation studies in sheep in vivo, rat mast cell activation using bronchoprovocation studies in sheep in vivo, rat mast cells in vitro, and to show that toxin-induced pulmonary abnormality are reduced in vitro, and to show that toxin-induced pulmonary abnormalities are reduced in mast cell deficient animals (mice) compared with their normal lifter mates. The investigators expect the results of these experiments to pharmacologically characterize the mechanisms responsible for the spasmogenic effects of airborne toxin in the airway and to identify therapeutic drug interventions.

项目3：在过敏性和非过敏性气道（亚伯拉罕）描述（取自研究者的摘要）吸入佛罗里达州“红潮汐”毒素（从研究者的摘要中取出），在过敏性和非过敏性气道中引起的支气管和鼻反应的机制与人类的下层和上呼吸道症状相关使哮喘患者容易加剧该疾病。尽管先前的研究表明，毒素的呼吸作用是神经介导的，但研究者的最近（初步）研究表明，这些不良事件不仅涉及神经元成分，而且涉及非神经元（MAS细胞）介导的成分。因此，在拟议的项目中，调查人员将通过从胆碱能和去甲肾上腺素中释放乙酰胆碱来测试：1）吸入毒素平滑肌和气道血管平滑肌，从胆碱能和去甲肾上腺素中释放出肾上腺素能神经元，从而激活肌肉和alpha-腺苷 - 脑脑元素的受体，并在及时及其及时的供供供供供供供供体系的受体。具有平滑肌肉作用的介体有助于神经介导的作用，2）毒素诱导的空气（上和下部）反应在动物（绵羊）中增强，其过敏性炎症是人类哮喘和过敏性鼻炎的“模型”。 These hypothesis will be tested with the following specific aims: 1a) to compare the effect of inhaled of inhaled toxin on bronchial airway smooth muscle (bronchoconstriction and airway hyperreponsiveness), mucocilliary clearance (bronchoconstriction and airway hyperreponsiveness), mucocilliary clearance, and airway vascular smooth muscle tone (bronchial blood flow) in vivo,在有或没有过敏性气道炎症的绵羊中，1B）评估通过模型的药物对支气管收集剂，粘膜循环和血管反应的修饰，这些药物干扰了毒素作用的拟议机制，以及1C），以评估标准支气管降低的可能性，以预防或屈服于对空气生毒素的抗反应的标准性抗反应。 2）比较鼻腔施用毒素对过敏和非过敏绵羊鼻气道耐药性的影响，以评估通过模型的药物来评估鼻反应的修饰，这些药物会干扰毒素作用的拟议机制，并评估标准疗法可预防或刺激标准治疗的可能性。 3）为确定绵羊在体内绵羊中使用支气管化的研究研究，在体内使用支气管前体研究的大鼠肥大细胞激活的大鼠肥大细胞激活的机制（小鼠）与正常的升降机伴侣相比。研究人员期望这些实验的结果在药理学上表征了导致气载毒素在气道中痉挛作用并确定治疗性药物干预措施的机制。