VIP AND NO IN AIRWAY INFLAMMATION AND ASTHMA

气道炎症和哮喘中的 VIP 和 NO

• 批准号: 2872938
• 负责人: SAMI I SAID
• 金额: $ 18.86万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2872938
• 关键词: NMDA receptors; asthma; bronchospasm; disease /disorder prevention /control; guinea pigs; human subject; immunofluorescence technique; in situ hybridization; inflammation; nitric oxide; nucleic acid probes; pathologic process; radioimmunoassay; respiratory function; smooth muscle; vasoactive intestinal peptide

DESCRIPTION: The broad, long-term goals are to improve our understanding of the mechanisms of the pathogenesis of bronchial asthma and to design more effective means of its prevention and management. The underlying general hypothesis is that neuropeptides and other neurotransmitters contribute to both the pathogenesis and modulation of the hyperreactivity, inflammation and smooth muscle proliferation of asthmatic airways. The proposal will test the following specific hypotheses regarding two transmitters, vasoactive intestinal peptide (VIP) and nitric oxide (NO): 1) As cotransmitters of non-adrenergic, non-cholinergic relaxation, VIP and NO modulate the bronchoconstriction and airway hyperreactivity of asthma; 2) VIP modulates the airway inflammation and smooth muscle proliferation of ronchial asthma; 3) Constitutive neuronal NO production may be deficient in asthma, predisposing to airway constriction and hyperreactivity, while inducible NO synthesis may be excessively stimulated in other sites, thereby promoting airway inflammation; and 4) The expression of VIP or its receptor may be deficient in asthmatic airways. To achieve these goals, experiments are designed to measure: 1) The co-expression of VIP and neuronal NO synthase in the same neurons, their co-release during electrical field stimulation of tracheal segment, and the possible interactions among VIP and NO, and their signal transduction pathways; 2) the stimulated production of VIP by the lung, and the increased expression of VIP and neuronal synthase in immunologic, neurogenic, and environmental models of airway inflammation induced in vivo and in guinea pig lung by antigen challenge, capsaicin, ozone and activation of NMDA receptors; 3) the attenuation by VIP and NO synthase inhibitors of airway inflammation and obstruction in these models, and the relationship of such attenuation to action at the tachykinin receptors; 4) the inhibition by VIP of the proliferation of human airway smooth muscle cells in culture; 5) the expression and distribution of neuronal and inducible NO synthases in biopsy samples from asthmatic airways, examined by immunocytochemical techniques (NO synthase antibody), by the NADPH-diaphorase reaction, and by molecular probes; and 6) the possible deficiency of VIP or its receptor in asthmatic airways, assessed by radioimmunoassay in bronchial tissue and BAL fluid from asthmatic and nonasthmatic subjects by immunofluorescence, molecular probes, and in situ hybridization.

描述：广泛的长期目标是提高我们的理解 支气管哮喘发病机制的研究及设计 更有效的预防和管理手段。 底层的 一般假设是神经肽和其他神经递质 有助于发病机制和调节 过度反应、炎症和平滑肌增殖 哮喘气道。 该提案将测试以下具体内容 关于两种递质血管活性肠肽的假设 (VIP) 和一氧化氮 (NO)：1) 作为非肾上腺素能的共同递质， 非胆碱能松弛、VIP 和 NO 调节支气管收缩 和哮喘气道高反应性； 2）VIP调节气道 支气管哮喘的炎症和平滑肌增殖； 3） 哮喘患者的组成性神经元 NO 生成可能不足， 易诱发气道收缩和高反应性，同时可诱导 其他部位的 NO 合成可能会受到过度刺激，从而 促进气道炎症； 4) VIP或其含义的表达 哮喘气道中的受体可能存在缺陷。 为了实现这些目标， 实验旨在测量：1）VIP 和 同一神经元中的神经元 NO 合酶，它们在 气管段的电场刺激，以及可能的 VIP和NO之间的相互作用及其信号转导途径； 2）刺激肺部产生VIP，并增加 VIP 和神经元合酶在免疫学、神经源性和 体内和体内诱导的气道炎症环境模型 通过抗原激发、辣椒素、臭氧和活化对豚鼠肺进行研究 NMDA 受体； 3) VIP和NO合酶抑制剂的减弱作用 这些模型中气道炎症和阻塞的情况，以及 这种衰减与速激肽受体作用的关系； 4) VIP对人气道平滑肌增殖的抑制作用 培养中的肌肉细胞； 5）神经元的表达和分布 以及哮喘气道活检样本中的诱导型一氧化氮合酶， 通过免疫细胞化学技术（NO合酶抗体）进行检查， NADPH-心肌黄酶反应，并通过分子探针； 6) 可能的 哮喘气道中 VIP 或其受体的缺乏，通过以下方法评估 对哮喘和哮喘患者的支气管组织和支气管肺泡灌洗液进行放射免疫分析 通过免疫荧光、分子探针和在非哮喘受试者中 原位杂交。