KININS AS MEDIATORS OF HUMAN REACTIONS

我们的中心前提是激肽是炎症的重要介质 人类呼吸道的反应，如哮喘、过敏和病毒 鼻炎。这是基于在这些过程中激肽生成的证据 条件和缓激肽诱导相关症状的能力 当涂在呼吸道粘膜上时。缓激肽的作用机制 然而，人们对人类呼吸道引起的症状知之甚少。我们 假设激肽对呼吸道功能的某些影响是通过以下途径实现的 感觉神经的刺激，以及这些神经的反应性 在呼吸道炎症过程中会增强。我们还假设阻止 激肽的作用将调节糖尿病的症状和发病机制。 哮喘和鼻炎。我们将使用以下方法来检验这些假设：1)单边 鼻腔刺激直接监测气流、血浆的变化 分泌物和反射性腺体分泌物。研究激肽在人类免疫系统中的作用 哮喘，我们将使用全肺激发来研究支气管收缩 和咳嗽，以及3)支气管腔内激发以检查激肽对 下呼吸道周围气道阻力与血管通透性的关系 航空公司。 在上呼吸道，我们将比较缓激肽的作用 多年生犀牛、正常犀牛和季节性犀牛的挑衅 过敏原激发前后。我们将使用可以改变神经的药物 确定激肽的哪些活动可能是由神经元介导的功能 每组患者。神经反应性似乎在 多年生犀牛。我们将确定辣椒素的作用 C纤维和外用糖皮质激素的脱敏(以减少 炎症)，对这些受试者对缓激肽的反应。我们会 使用激动素受体拮抗剂Hoe 140证实其特异性 激肽在上呼吸道中的作用及确定激肽在 过敏性鼻炎和病毒性鼻炎的发病机制。 在较低的呼吸道，过敏原的能力是不同的 诱导对缓激肽反应性增强的挑战与 直接痉挛，乙酰甲胆碱。以确定是否增加了对 缓激肽反映增强的神经反应性，我们将研究 改变神经功能的药物对缓激肽反应的影响 过敏原激发前后。我们将确定过敏原诱导的 对缓激肽的反应性增加与反应性增加有关 其他刺激，据说是通过神经机制起作用的，也会 确定诱导对缓激肽的快速反应是否会降低对 这样的刺激。我们将确定激动素对外周呼吸道的影响 哮喘患者和正常人的阻力和血浆漏出。其影响 将研究糖皮质激素对哮喘患者激动素反应的影响。 最后，我们将使用HoE 140来确认激动素反应的特异性 并监测激肽在基线肺功能和 有症状的哮喘患者的反应性。 这些研究应该为激肽在体内的作用提供重要的见解。 哮喘和鼻炎的发病机制，并可能导致新的治疗方法 用于治疗这些病症。

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.