MECHANISMS OF ALLERGEN INDUCED AIRWAYS DYSFUNCTION

这个项目的目标是定义细胞和生化 模型中神经控制变化的机制 呼吸道功能障碍。在本授权期内工作 表明哮喘动物的呼吸道暴露于变应原 过敏原特异性IgE导致呼吸道显著改变 功能。这些变化中最突出的是胆碱能增强。 通过增加对呼吸道的释放而进入呼吸道 刺激神经时神经末梢的乙酰胆碱(ACh)。 此外，有一个显著的减少(过敏原 致敏)或功能丧失(过敏原致敏加 呼吸道接触变应原)神经介导的呼吸道 松弛通路：非肾上腺素能非胆碱能抑制 (Nanci)系统。这就产生了神经控制的不平衡 阻塞呼吸道的机制比 防止阻塞的机械装置。迄今为止在一只小鼠身上的研究 模型表明淋巴细胞在协调的过程中起关键作用 这些反应和嗜酸性粒细胞的涌入在以下方面很重要 改变ACh的释放。这项提议的一个主要目标是 研究嗜酸性粒细胞被吸入呼吸道的机制 并改变呼吸道功能。作为这些研究的一部分，我们将 定义主单元对这一系列事件的贡献。 这一系列实验将利用两位博士的专业知识。 Gelfand(过敏原特异性单抗)和Irvin (小鼠的肺部生理学)。的能力 增加ACh释放的聚阳离子将直接通过 这种神经递质的测量。卡尔·怀特博士的研究 也将使用转基因小鼠来评估 有毒氧物种对胆碱能的贡献 上面提到的异常情况。在功能损失方面 NANCI系统，环3‘，5’-腺苷一磷酸的变化 可能是T细胞因子诱导的途径，其结果是 过敏原敏感化和挑战将与Dr。 加里·约翰逊。磷酸二酯酶活性的变化 呼吸道内的酶和G蛋白 在评估中将衡量过敏原敏感度和挑战性 这条路。哺乳动物呼吸道生物学的这些研究 通过允许我们在此项目中 问一些根本不可能解决的机械问题 人类。

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.