MECHANISMS OF ALLERGEN INDUCED AIRWAYS DYSFUNCTION

过敏原引起的气道功能障碍的机制

• 批准号: 6241922
• 负责人: GARY L LARSEN
• 金额: $ 26.84万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6241922
• 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.

这个项目的目标是定义细胞和生物化学 负责模型中神经控制改变的机制 呼吸道功能障碍 在本赠款期内的工作 证明了在动物中气道暴露于过敏原， 过敏原特异性IgE导致气道显著改变 功能 这些变化中最突出的是增强的胆碱能 输入到气道，表现为增加释放 乙酰胆碱（ACh）从神经末梢刺激神经。 此外，有一个显着减少（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 松弛剂途径：非肾上腺素能非胆碱能抑制性 （NANCi）系统。 这会造成神经控制的不平衡， 阻塞气道的机制比 防止阻塞的机制。 迄今为止在小鼠中进行的研究 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是重要的， 改变乙酰胆碱的释放 这项建议的一个主要目标是 研究嗜酸性粒细胞被吸入气道的机制 改变气道功能 作为这些研究的一部分，我们将 明确肥大细胞在这一系列事件中的作用。 这一系列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 （鼠种内的肺生理学）。 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。 卡尔白色博士的研究 也将使用转基因小鼠来评估 有毒氧对胆碱能的贡献 上面提到的异常。 在功能丧失方面， NANCi系统，环3 '，5'-腺苷酸的变化 可能是T细胞丝氨酸诱导的途径， 过敏原致敏和激发将由Dr. 加里约翰逊。 磷酸二酯酶活性的改变 酶以及G蛋白在气道内作为一个结果， 过敏原致敏性和激发将在评估中进行测量 这条路。 这些哺乳动物气道生物学的研究 补充临床项目在这个程序中，让我们 问一些基本的机械性问题，这些问题是不可能在 人类