KININS AS MEDIATORS OF HUMAN REACTIONS

激肽作为人类反应的调节剂

• 批准号: 2668650
• 负责人: David Proud
• 金额: $ 27.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-12 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2668650
• 关键词: asthma; bradykinin; bronchomotion; exudate /transudate; human subject; inflammation; kinins; membrane permeability; respiratory hypersensitivity; respiratory reflex; rhinitis; secretion; vascular resistance

Our central premise is that kinins are important mediators of inflammatory reactions of the human airways, such as asthma, and allergic and viral rhinitis. This is based upon evidence of kinin generation during these conditions and on the ability of bradykinin to induce relevant symptoms when applied to the airway mucosa. The mechanisms by which bradykinin elicits symptoms in the human airways, however, are poorly understood. We hypothesize that some effects of kinins on airway function are mediated by stimulation of sensory nerves, and that the responsiveness of these nerves is enhanced during airway inflammation. We also hypothesize that blocking the actions of kinins will modulate the symptoms and pathogenesis of asthma and rhinitis. We will test these hypotheses using: 1) Unilateral nasal provocation to directly monitor changes in airflow, plasma exudation, and reflex glandular secretion. To study the role of kinins in asthma, we will use 2) whole lung challenge to study bronchoconstriction and cough, and 3) endobronchial challenge to examine effects of kinins on peripheral airway resistance and on vascular permeability in the lower airways. In the upper airways, we will compare the effects of bradykinin provocation in perennial rhinitics, normals, and in seasonal rhinitics before and after allergen challenge. We will use agents that modify nerve function to determine which actions of kinins may be neurally mediated in each patient group. Neural responsiveness seems to be increased in perennial rhinitics. We will determine the effects of capsaicin desensitization of C-fibers, and of topical glucocorticoids (to reduce inflammation), on the responses of these subjects to bradykinin. We will use the kinin receptor antagonist, Hoe 140, to confirm the specificity of kinin effects in the upper airways and to determine the role of kinins in the pathogenesis of allergic and viral rhinitis. In the lower airways, there are differences in the ability of allergen challenge to induce increased reactivity to bradykinin compared to the direct spasmogen, methacholine. To determine if increased reactivity to bradykinin reflects enhanced neural responsiveness, we will examine the effects of agents that alter nerve function on responses to bradykinin before and after allergen challenge. We will determine if allergen-induced increased reactivity to bradykinin is associated with increased reactivity to other stimuli that reportedly act via neural mechanisms and will also determine if inducing tachyphylaxis to bradykinin reduces the response to such stimuli. We will define the effects of kinins on peripheral airway resistance and plasma transudation in asthmatics and normals. The effects of glucocorticoids on responses of asthmatics to kinins will be examined. Finally, we will use Hoe 140 to confirm the specificity of kinin responses and to monitor the role of kinins in baseline pulmonary function and reactivity of symptomatic asthmatics. These studies should provide important insights into the role of kinins in the pathogenesis of asthma and rhinitis and may lead to novel therapies for the treatment of these conditions.

我们的中心前提是激肽是炎症反应的重要介质， 人体呼吸道的反应，如哮喘，过敏和病毒 鼻炎这是基于在这些过程中产生激肽的证据。 条件和缓激肽诱导相关症状的能力 当应用于气道粘膜时。缓激肽 然而，人们对人类气道中的过敏症状知之甚少。我们 假设激肽对气道功能的某些作用是由 刺激感觉神经，这些神经的反应性 在气道炎症时增强。我们还假设， 激肽的作用将调节的症状和发病机制 哮喘和鼻炎。我们将测试这些假设使用：1）单边 鼻激惹，以直接监测气流、血浆 渗出和反射性腺体分泌。为了研究激肽在 哮喘，我们将使用2）全肺激发来研究支气管收缩 和咳嗽，和3）支气管内激发，以检查激肽对 外周气道阻力和下呼吸道血管通透性 航空公司. 在上呼吸道，我们将比较缓激肽 常年性鼻炎患者、正常人和季节性鼻炎患者的激发 在过敏原激发前后。我们会用能改变神经的药剂 功能，以确定哪些行动的激肽可能是神经介导的， 每个患者组。神经反应性似乎在 常年性鼻炎我们将确定辣椒素的作用 C纤维脱敏和局部糖皮质激素（以减少 炎症），这些受试者对缓激肽的反应。我们将 使用激肽受体拮抗剂Hoe 140，以确认 激肽在上气道中的作用，并确定激肽在 过敏性鼻炎和病毒性鼻炎的发病机制。 在下呼吸道，过敏原的能力存在差异， 激发，以诱导对缓激肽的反应性增加， 直接致痉挛剂乙酰甲胆碱为了确定是否增加了对 缓激肽反映了增强的神经反应，我们将研究 改变神经功能的药物对缓激肽反应的影响 在过敏原激发前后。我们将确定是否过敏原引起的 对缓激肽的反应性增加与 据报道，其他刺激通过神经机制起作用， 确定诱导对缓激肽的快速耐受是否会降低对 这样的刺激。我们将明确激肽对外周气道的影响 哮喘患者和正常人的阻力和血浆渗出。的影响 糖皮质激素对哮喘患者对激肽反应的影响。 最后，我们将使用Hoe 140来确认激肽反应的特异性 并监测激肽在基线肺功能中的作用， 有症状的哮喘患者的反应性。 这些研究应该提供重要的见解激肽的作用， 哮喘和鼻炎的发病机制，并可能导致新的治疗方法 来治疗这些疾病。