Bronchodilation & Anti-Inflammatory Response by VIP

支气管扩张

• 批准号: 6918658
• 负责人: ANTHONY M SZEMA
• 金额: $ 14.07万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918658
• 关键词: active immunization; adenylate cyclase; anaphylaxis; antiinflammatory agents; asthma; biological signal transduction; bronchodilators; capsaicin; chemokine; clinical research; cyclic AMP; cytokine; disease /disorder model; enzyme activity; gene deletion mutation; gene expression; genetically modified animals; immune response; immunomodulators; laboratory mouse; methacholine; neuropeptide receptor; nuclear factor kappa beta; protein kinase A; respiratory epithelium; vasoactive intestinal peptide

DESCRIPTION (provided by applicant): Airway constriction and inflammation are key components of asthma and anaphylaxis. This research aims to improve our understanding of the pathogenesis of these responses, and to identify more effective means of their modulation or prevention, using the neuropeptide vasoactive intestinal peptide (VIP) as a prototype test drug. Specific Aims: 1) Test the hypothesis that VIP is an endogenous modulator of airway constriction; 2) Test the hypothesis that VIP is an endogenous modulator of airway inflammation; 3) Test the hypothesis that VIP suppresses inflammation by a dual action-suppressing inflammatory cell activity and inhibiting NF-kappaB activation and consequent production of inflammatory cytokines; and 4) Test the hypothesis that VIP's actions are mediated by VPAC1 and VPAC2 receptors and resultant stimulation of the adenylate cyclase/protein kinase A (PKA) pathway. These aims will be tested in 2 models of airway constriction and inflammation, induced by anaphylaxis and by capsaicin, in isolated lungs and in vivo. The animals will be wild-type mice and mice with overexpression of VPAC1 and VPAC2 receptor, or with targeted deletion of the VIP gene (VIPKO) or of the VPAC1 or VPAC2 receptor (VPACKO). For Aim 1, we expect to determine that airway constriction induced by specific stimuli is alleviated in mice with overexpression of VIP receptors, and exaggerated in VIPKO or VPACKO mice, and that catalytic antibodies against VIP enhance airway constriction. For Aim 2, we expect to show that VIP is released in response to airway inflammation, and that airway inflammation is reduced in mice with overexpression of either of the 2 VIP receptors, and exaggerated in VPACKO mice or by catalytic antibodies against VIP. For Aim 3, we will seek evidence that VIP suppresses inflammatory cell accumulation in the airways of late-phase asthma models, and inhibits NF-kappaB activation and consequent production of inflammatory cytokines and chemokines. For Aim 4, the dominant receptors will be identified by testing the effects of selective VPAC1 and VPAC2 receptor agonists and by use of VPAC transgenic mice, and the importance of the postulated signal transduction pathway will be assessed by measuring VIP-induced cyclic AMP production and PKA activation, and the extent to which PKA inhibitors reduce the modulatory influence of VIP on airway constriction and inflammation. Significance: The knowledge gained from these studies should provide insights into the mechanisms of asthmatic/anaphylactic responses and may suggest new therapeutic options for these conditions.

描述（由申请人提供）： 气道收缩和炎症是哮喘和过敏反应的关键组成部分。 本研究旨在使用神经肽血管活性肠肽（VIP）作为原型测试药物，提高我们对这些反应发病机制的理解，并确定更有效的调节或预防方法。 具体目标： 1) 检验 VIP 是气道收缩的内源性调节剂的假设； 2）检验VIP是气道炎症内源性调节剂的假设； 3）检验VIP通过双重作用抑制炎症的假设——抑制炎症细胞活性和抑制NF-kappaB激活以及随后产生的炎症细胞因子； 4) 检验 VIP 的作用是由 VPAC1 和 VPAC2 受体介导的假设以及由此产生的腺苷酸环化酶/蛋白激酶 A (PKA) 途径的刺激。 这些目标将在由过敏反应和辣椒素诱导的离体肺部和体内的两种气道收缩和炎症模型中进行测试。 这些动物将是野生型小鼠和VPAC1和VPAC2受体过度表达的小鼠，或者VIP基因(VIPKO)或VPAC1或VPAC2受体(VPACKO)的靶向删除的小鼠。 对于目标 1，我们期望确定由特定刺激引起的气道收缩在 VIP 受体过度表达的小鼠中减轻，而在 VIPKO 或 VPACKO 小鼠中加剧，并且针对 VIP 的催化抗体增强气道收缩。 对于目标 2，我们希望证明 VIP 是响应气道炎症而释放的，并且在 2 个 VIP 受体过度表达的小鼠中，气道炎症减轻，而在 VPACKO 小鼠中或通过针对 VIP 的催化抗体过度表达，气道炎症加剧。 对于目标 3，我们将寻求证据证明 VIP 可以抑制晚期哮喘模型气道中炎症细胞的积累，并抑制 NF-κB 的激活以及随后产生的炎症细胞因子和趋化因子。 对于目标 4，将通过测试选择性 VPAC1 和 VPAC2 受体激动剂的作用以及使用 VPAC 转基因小鼠来鉴定主要受体，并且将通过测量 VIP 诱导的环 AMP 产生和PKA 激活，以及 PKA 抑制剂降低 VIP 对气道收缩和炎症的调节影响的程度。 意义：从这些研究中获得的知识应该可以深入了解哮喘/过敏反应的机制，并可能为这些疾病提出新的治疗选择。