NEUROGENIC INFLAMMATION IN ASTHMA AND OZONE LUNG INJURY

哮喘的特征是发作性的支气管收缩，慢性肺 炎症和对收缩刺激的高反应性。气道口 哮喘中的炎症被认为是导致 疾病的发病机制，但潜在的分子机制 哮喘中发生的炎症尚不清楚。空气污染物， 包括臭氧在内，都被报道会加重哮喘和相关的 炎症，但污染物对环境影响的机制 哮喘的病理机制尚不清楚。因为有很多潜力 参与的炎症介质，还不可能在 哪些分子在肿瘤的发展中起着机械性的作用 这种疾病。这里提出的研究将检测感觉神经肽。 已知的速激肽可以作为炎症介质。速激肽 包括神经肽P物质和神经激动素A，它们发挥其 通过与神经激肽受体结合而产生的效应。速激肽水平 哮喘肺组织中P物质含量增加，肺组织中P物质释放。 过敏原或臭氧暴露后的人类。核心假设是 这里测试的是从感觉神经释放的速激肽神经肽 末端是过敏原和臭氧诱导的发展过程中的关键媒介 呼吸道发炎。这一假设将通过使用转基因和 基因敲除技术控制感觉神经纤维量 对小白鼠的肺部进行神经支配。在人体内发展的炎症 这些基因改变的小鼠在暴露于变应原或 臭氧，或两种试剂的组合，将通过以下方式测量 组织学、生化和细胞学方法。我们的假设 预测小鼠释放更多的速激肽将是 异常易受过敏原和臭氧诱导的呼吸道炎症和 释放数量减少的速激肽的小鼠将对他产生抗药性 炎症的发展。拟议中的实验将允许 确定臭氧和过敏原是否协同作用产生 炎症以及速激肽是否参与这些作用 单独或组合在一起的代理。此外，这些分子 速激肽发挥作用的途径将在 基因操控的小鼠。例如，神经激肽受体拮抗剂 将被用来表征介导神经源性的受体亚型 老鼠体内的炎症会增加速激肽的释放。 还将使用分子生物学和生化方法来确定 细胞因子mRNAs和蛋白产物的表达是否发生改变 小鼠释放的速激素量增加或减少。这部小说 利用基因操作的小鼠的方法将提供有价值的 速激肽致炎机制的研究进展 呼吸道疾病。

Asthma is characterized by episodic bronhoconstriction, chronic lung inflammation, and airway hyperreactivity to constricting stimuli. Airway inflammation in asthma is thought to be a critical factor in the pathogenesis of the disease, but the molecular mechanisms underlying the inflammation that develops in asthma are not known. Airborne pollutants, including ozone, have been reported to worsen asthma and associated inflammation, but the mechanisms by which pollutants contribute to the pathology of asthma are not known. Since there are many potential inflammatory mediator involved, it has not been possible to establish in vivo which molecules are playing a mechanistic role in the development of the disease. The studies proposed here will examine sensory neuropeptides known a tachykinins that can act as inflammatory mediators. Tachykinins include the neuropeptides substance P and neurokinin A, which exert their effects by binding to neurokinin receptors. Levels of the tachykinin substance P are increased in asthmatic lung, and substance P is released in humans after allergen or ozone exposure. The central hypothesis to be tested here is that tachykinin neuropeptides released from sensory nerve endings are key mediators in the development of allergen- and ozone-induced airway inflammation. The hypothesis will be tested by using transgenic and gene knock-out technology to manipulate the amount of sensory nerve fibers that innervate the lungs of mice. The inflammation that develops in the lungs of these genetically altered mice after exposure to allergen or ozone, or a combination of the two agents, will be measured by histological, biochemical, and cytological methods. Our hypothesis predicts that mice releasing increased amounts of tachykinins will be unusually susceptible to allergen-and ozone-induced airway inflammation and that mice releasing reduced amounts of tachykinins will be resistant tot he development of inflammation. The propose experiments will allow a determination of whether ozone and allergen act synergistically to produce inflammation and whether tachykinins are involved in the action of these agents, either individually or in combination. In addition, the molecules through which tachykinins exert their effects will be examined in the genetically manipulated mice. For example, neurokinin receptor antagonists will be used to characterize receptor subtypes mediating neurogenic inflammation in mice that release increased amounts of tachykinins. Molecular biological and biochemical methods will also be used to determine whether expression of cytokine mRNAs and protein products are altered in mice releasing increased or reduced amounts of tachykinins. This novel approach employing genetically manipulated mice will provide valuable mechanistic information concerning inflammation induced by tachykinins in airway disease.