KININS AS MEDIATORS OF HUMAN REACTIONS

这项提案的目的是确定激肽的重要性 作为人类过敏性和炎症性疾病的介质。 我们有 显示激肽在鼻分泌物中产生， 对过敏原激发的即时和晚期反应， 有症状的个体对感冒鼻攻击的反应， 干燥的空气，以及在有症状的鼻病毒感染期间。 我们将 评估激肽在发病机制中的作用程度 这些不同类型的鼻炎和哮喘，并将描绘 这些过程中激肽形成和破坏的机制 条件 我们最近的研究表明， 缓激肽会引起鼻炎和喉咙痛的症状， 强有力地支持了激肽在 上呼吸道的炎症反应。 我们会研究 激肽诱导这些症状的机制。 确定 激肽在鼻炎中的病理生理作用，我们将进行 血管紧张素转换酶抑制剂的研究 试图减少激肽的破坏，并确定是否增加 激肽水平与症状的增加有关， 用抗原、寒冷、干燥空气或鼻病毒攻击。 我们还将 研究一种新的竞争性激肽拮抗剂（DArg 0- Hyp 3-DPhe 7-缓激肽）抑制鼻激发的作用 用激肽 如果这种化合物被证明是有效的抑制剂 在体内对激肽激发的反应，它将用于 阐明激肽在多大程度上有助于 在我们的每个模型系统中的鼻炎病理学。 我们在阐明这些机制方面取得了实质性进展， 激肽的形成和代谢过程中的即时反应， 过敏原挑战，但有证据表明，这些机制可能 在晚期过敏反应和症状性过敏反应期间， 鼻病毒感染 我们将进行比较生化 分析，以确定调节激肽水平的机制 各种类型的鼻炎。 由于腺激肽释放酶在 在速发型变态反应中激肽形成中的作用 鼻子，我们将局部腺激肽释放酶在上部 并将决定哪些因素控制激肽释放酶 分泌物 最后，我们将继续研究， 激肽在下呼吸道炎症性疾病中的作用， 哮喘 我们会在下呼吸道局部注射腺激肽释放酶 并将激肽释放酶和激肽水平与 和对节段性（局部）激发的晚期临床反应， 肺 我们还将研究激肽降解的机制 在下呼吸道 这些研究将大大增加我们对 激肽在人类过敏和炎症反应，并可能导致 新的治疗方法来对抗这些疾病。

The goal of this proposal is to determine the importance of kinins as mediators of human allergic and inflammatory diseases. We have shown that kinins are generated in nasal secretions during both the immediate and late responses to allergen challenge, during the response of symptomatic individuals to nasal challenge with cold, dry air, and during symptomatic rhinovirus infections. We will evaluate the extent to which kinins contribute to the pathogenesis of these different types of rhinitis and asthma and will delineate the mechanisms of kinin formation and destruction during these conditions. Our recent demonstration that nasal provocation with bradykinin induces symptoms of rhinitis and a sore throat lends strong support to the hypothesis that kinins play an important role in inflammatory reactions of the upper airways. We will study the mechanisms by which kinins induce these symptoms. To determine the pathophysiological role of kinins in rhinitis, we will perform studies using angiotensin converting enzyme inhibitors in an attempt to reduce kinin destruction and to determine if increases kinin levels are associated with an increase in symptoms upon challenge with antigen, cold, dry air or rhinovirus. We will also study the ability of a new, competitive kinin antagonist (DArg0- Hyp3-DPhe7-bradykinin) to inhibit the effects of nasal challenge with kinins. If the compound proves to be an effective inhibitor of the response to kinin challenge in vivo, it will be used to elucidate the extent to which kinins contribute to the symptomatology of rhinitis in each of our model systems. We have made substantial progress in elucidating the mechanisms of kinin formation and metabolism during the immediate response to allergen challenge but have evidence that these mechanisms may differ during the late allergic response and during symptomatic rhinovirus infections. We will perform comparative biochemical analyses to determine the mechanisms regulating kinin levels in each type of rhinitis. Since glandular kallikrein plays a major role in kinin formation during the immediate allergic reaction in the nose, we will localize glandular kallikrein in the upper airways and will determine which factors control kallikrein secretion. Finally, we will continue our studies to determine the importance of kinins in inflammatory diseases of the lower airways, such as asthma. We will localize glandular kallikrein in the lower airways and will correlate kallikrein and kinin levels with the immediate and late clinical responses to segmental (localized) challenge in the lung. We will also study the mechanisms of kinin degradation in the lower airways. These studies will greatly increase our understanding of the role of kinins in human allergic and inflammatory reactions and may lead to new therapeutic approaches to combat these diseases in man.