MECHANISMS OF ALLERGEN INDUCED AIRWAYS DYSFUNCTION

过敏原引起的气道功能障碍的机制

• 批准号: 6109833
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6109833
• 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.

该项目的目的是定义细胞和生化 负责模型中神经控制改变的机制 气道功能障碍。 在当前赠款期间工作 证明气道暴露于动物中 过敏原特异性IgE导致气道发生重大变化 功能。 这些变化中突出的是增强的胆碱能 通过增加的释放，向气道输入 神经刺激后神经末端的乙酰胆碱（ACH）。 另外，有显着降低（过敏原 敏化）或功能丧失（过敏原敏化加上 气道神经介导的过敏原暴露 放松途径：非肾上腺素能抑制性抑制作用 （Nanci）系统。 这会导致神经控制不平衡 阻碍气道的机制比 防止阻塞的机制。 迄今为止的研究 模型表明淋巴细胞在编排中至关重要 这些反应以及嗜酸性粒细胞的涌入在术语中很重要 改变ACH释放。 该提议的一个主要目标是 研究将嗜酸性粒细胞吸入气道的机制 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级联事件的贡献。 这一系列实验将利用这两个DR的专业知识。 Gelfand（过敏原特异性单克隆抗体）和Irvin （鼠类种类内的肺部生理）。 能力 增加ACh释放的多阳离子将直接解决 该神经递质的测量。 卡尔·怀特博士的研究 还将进行使用转基因小鼠评估 有毒氧对胆碱能的贡献 上面指出的异常。 在功能损失方面 Nanci系统，循环3'，5'-腺苷单磷酸盐的变化 可能是T细胞因子诱导的途径。 过敏原致敏和挑战将与博士解决。 加里·约翰逊。 磷酸二酯酶活性的改变 由于 过敏原敏化和挑战将在评估中衡量 这条路。 这些对哺乳动物物种气道生物学的研究 通过允许我们来补充该计划中的临床项目 询问基本的机械问题，这些问题无法解决 人类。