MECHANISMS OF ALLERGEN INDUCED AIRWAYS DYSFUNCTION

过敏原引起的气道功能障碍的机制

• 批准号: 6327728
• 负责人: GARY L LARSEN
• 金额: $ 28.58万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6327728
• 关键词: acetylcholine; adenosine monophosphate; allergens; asthma; cytokine; disease /disorder model; eosinophil; free radical oxygen; genetic strain; immunoglobulin E; inflammation; laboratory mouse; laboratory rabbit; mast cell; monoclonal antibody; neuroimmunomodulation; neuroregulation; neurotransmitter transport; plethysmography; respiratory epithelium; respiratory function; respiratory hypersensitivity

The objective of this project is to define cellular and biochemical mechanisms responsible for alterations in neural control in models of airways dysfunction. Work during the current grant period demonstrates that airway exposure to allergen in animals with allergen-specific IgE leads to significant alterations in airway function. Prominent among these changes is enhanced cholinergic input into airways as manifest by increased release of acetylcholine (ACh) from nerve endings upon stimulation of nerves. In addition, there is a significant decrease (allergen sensitization) or loss in function (allergen sensitization plus airway exposure to allergen) of the airway neurally mediated relaxant pathway: the nonadrenergic noncholinergic inhibitory (NANCi) system. This produces an imbalance in neural control in that mechanisms that obstruct airways are more prominent than mechanisms that prevent obstruction. Studies to date in a murine model suggest lymphocytes are critical in the orchestration of these responses, and an influx of eosinophils is important in terms of altering ACh release. A major objective of this proposal is to study the mechanisms by which eosinophils are drawn into the airway and alter airway function. As part of these studies, we will define the contribution of mast cells to this cascade of events. This series of experiments will utilize the expertise of both Drs. Gelfand (allergen-specific monoclonal antibodies) and Irvin (pulmonary physiology within murine species). The ability of polycations to increase ACh release will be addressed directly by measurement of this neurotransmitter. Studies with Dr. Carl White will also be conducted that use transgenic mice to assess the contribution of toxic oxygen species to the cholinergic abnormalities noted above. In terms of functional loss of the NANCi system, changes in the cyclic 3',5'-adenosine monophosphate pathway that may be T cell cytokine-induced as a consequence of allergen sensitization and challenge will be addressed with Dr. Gary Johnson. Alterations in the activity of phosphodiesterase enzymes as well as G proteins within airways as a consequence of allergen sensitization and challenge will be measured in assessing this pathway. These studies of airway biology in mammalian species complement the clinical projects in this program by allowing us to ask basic mechanistic questions that are impossible to address in humans.

该项目的目标是定义细胞和生化 模型中神经控制改变的机制 气道功能障碍。 当前补助期内的工作 表明患有过敏原的动物的气道暴露 过敏原特异性 IgE 导致气道发生显着改变 功能。 这些变化中最突出的是胆碱能增强 气道的输入表现为增加的释放 神经受到刺激后，神经末梢会产生乙酰胆碱（ACh）。 此外，还有显着减少（过敏原 致敏）或功能丧失（过敏原致敏加 气道暴露于过敏原）的气道神经介导 松弛途径：非肾上腺素能非胆碱能抑制 （NANCi）系统。 这会导致神经控制失衡 阻塞气道的机制比 防止阻塞的机制。 迄今为止对小鼠的研究 模型表明淋巴细胞在协调 这些反应，以及嗜酸性粒细胞的流入对于 改变乙酰胆碱的释放。 该提案的一个主要目标是 研究嗜酸性粒细胞被吸入气道的机制 并改变气道功能。 作为这些研究的一部分，我们将 定义肥大细胞对这一系列事件的贡献。 这一系列的实验将利用两位博士的专业知识。 Gelfand（过敏原特异性单克隆抗体）和 Irvin （鼠科动物的肺生理学）。 的能力 聚阳离子增加乙酰胆碱释放将直接解决 测量这种神经递质。 与卡尔·怀特博士一起研究 还将使用转基因小鼠来评估 有毒氧对胆碱能的贡献 上述异常情况。 在功能丧失方面 NANCi 系统，环状 3',5'-单磷酸腺苷的变化 可能是 T 细胞细胞因子诱导的途径 过敏原致敏和挑战将由博士解决。 加里·约翰逊。 磷酸二酯酶活性的改变 气道内的酶和 G 蛋白 在评估中将测量过敏原致敏性和挑战 这条途径。 这些哺乳动物气道生物学研究 通过让我们能够补充该计划中的临床项目 提出无法解决的基本机械问题 人类。