KININS AS MEDIATORS OF HUMAN REACTIONS

激肽作为人类反应的调节剂

• 批准号: 6637448
• 负责人: BRENDAN J CANNING
• 金额: $ 14.3万
• 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 2003-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637448
• 关键词: acetylcholine; asthma; atopy; autonomic reflex; bradykinin; bronchomotion; clinical research; guinea pigs; human subject; immunocytochemistry; inflammation; leukocyte activation /transformation; mucosa; neuroimmunomodulation; nitric oxide synthase; respiratory epithelium; respiratory hypersensitivity; rhinitis

Bradykinin (BK) is a potent proinflammatory peptide that has been implicated in the pathogenesis of rhinitis and asthma. Despite the potential importance of this peptide in airway diseases, however, the mechanisms by which BK exerts its effects in the airways are poorly understood. We have shown that the airways of subjects with active allergic disease are hyperreactive to BK and that this hyperreactivity is mediated by neural reflexes that are not observed in the airways of asymptomatic subjects. BK appears to be unique in this regard. We can reproduce this hyperreactivity experimentally using repeated localized allergen challenge. This proposal will combine in vivo studies in human upper and lower airways with complementary studies in an in vivo guinea pig model (in which reflex components can be further dissected) to perform the first rigorous analysis of how neural responses to BK are altered in allergic disease, and to begin to delineate which components of allergic inflammation underly these altered neural responses. Allergic inflammation could enhance airway responses to BK at one or more sites along the reflex pathway. We will determine whether allergic inflammation enhances airway responsiveness to BK by: 1) sensitizing afferent nerve terminals innervating the airway mucosa; 2) acting on the efferent limb of airway parasympathetic nerves to increase cholinergic and/or impair noncholinergic (NANC) effector responses; or 3) altering the central processing of airway afferent activity or altering synaptic transmission in airway parasympathetic ganglia. We will establish whether the ability to induce neural responsiveness to BK is a unique feature of allergic inflammation, by determining whether experimental rhinovirus infection of normal subjects also induces neural hyperreactivity to BK. Based on the results of such studies, we will determine whether to focus further on the role of inflammatory components that are characteristic of allergic inflammation (e.g. mast cell/eosinophil products, selected cytokines) in the alteration of neural responsiveness or to examine other inflammatory components. These rigorous studies will not only clarify the role of BK in airway diseases, but will also have broader relevance by providing new and important insights into how neural function is altered in asthma and rhinitis.

缓激肽(BK)是一种有效的促炎性多肽，已被 与鼻炎和哮喘的发病机制有关。尽管 这种多肽在呼吸道疾病中的潜在重要性， 然而，BK在体内发挥作用的机制 人们对航空公司知之甚少。我们已经证明了 患有活动性过敏性疾病的受试者对BK和 这种高反应性是由神经反射调节的， 在无症状受试者的呼吸道中未观察到。出现BK 在这方面是独一无二的。我们可以复制这个 反复定位过敏原实验中的高反应性 挑战。这项建议将结合人体内的研究。 上呼吸道和下呼吸道的体内互补研究 豚鼠模型(其中反射成分可进一步 解剖)进行第一次严格的神经性分析 在过敏性疾病中，对BK的反应会改变，并开始 描述这些过敏性炎症的哪些成分 改变了神经反应。 过敏性炎症可增强对BK的呼吸道反应 或更多的反射路径上的位置。我们将决定 过敏性炎症是否增强了对 BK通过：1)敏化支配 呼吸道粘膜；2)作用于呼吸道传出肢体 副交感神经增加胆碱能和/或损害胆碱能 非胆碱能(NaNC)效应器反应；或3)改变 呼吸道传入活动或改变的中央处理 呼吸道副交感神经节中的突触传递。 我们将确定是否有能力诱导神经 对BK的反应性是过敏的一个独特特征 炎症，通过确定实验性鼻病毒 正常受试者感染也会引起神经高反应性 致BK。根据这些研究的结果，我们将确定 是否应进一步关注炎性成分的作用 以过敏性炎症为特征的(如肥大 细胞/嗜酸性粒细胞产物、选定的细胞因子)在改变中 神经反应或检查其他炎症性疾病 组件。 这些严格的研究不仅将澄清BK在 呼吸道疾病，但也将具有更广泛的相关性 提供了关于神经功能如何的新的和重要的见解 在哮喘和鼻炎中发生改变。

项目成果

Observations on nasal late phase reactions.

鼻腔晚相反应的观察。

• DOI: 10.3109/08820138709087108
• 发表时间: 1987
• 期刊: Immunological investigations
• 影响因子: 2.8
• 作者: Naclerio,RM;Kagey-Sobotka,A;Lichtenstein,LM;Togias,AG;Iliopoulos,O;Pipkorn,U;Bascom,R;Norman,PS;Proud,D
• 通讯作者: Proud,D

A human lung mast cell chymotrypsin-like enzyme. Identification and partial characterization.

一种人肺肥大细胞胰凝乳蛋白酶样酶。

• DOI: 10.1172/jci112276
• 发表时间: 1986
• 期刊: The Journal of clinical investigation
• 作者: Wintroub,BU;Kaempfer,CE;Schechter,NM;Proud,D
• 通讯作者: Proud,D

The effects of H1 antihistamines on the early allergic response.

• 发表时间: 1989-12
• 期刊: Annals of allergy
• 作者: F. Baroody;D. Proud;A. Kagey-sobotka;L. Freidhoff;P. Norman;L. Lichtenstein;R. Naclerio

Kinins in the pathogenesis of human airway diseases.

激肽在人类气道疾病发病机制中的作用。

• 发表时间: 1994
• 期刊: Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
• 作者: Proud,D

Theophylline reduces the response to nasal challenge with antigen.

茶碱可降低对抗原鼻刺激的反应。

• DOI: 10.1016/0002-9343(85)90087-7
• 发表时间: 1985
• 期刊: The American journal of medicine
• 作者: Naclerio,RM;Bartenfelder,D;Proud,D;Togias,AG;Meyers,DA;Kagey-Sobotka,A;Norman,PS;Lichtenstein,LM
• 通讯作者: Lichtenstein,LM