NEUROGENIC INFLAMMATION IN ASTHMA AND OZONE LUNG INJURY

哮喘的特征是发作性支气管收缩，慢性肺 炎症和气道对收缩刺激的高反应性。 气道 哮喘中的炎症被认为是 疾病的发病机制，但潜在的分子机制 在哮喘中发展的炎症是未知的。 空气中的污染物， 包括臭氧，据报道会使哮喘恶化， 炎症，但污染物的机制有助于 哮喘的病理学尚不清楚。 因为有很多潜在的 炎症介质的参与，它还没有能够建立在 体内哪些分子在发育中起着机械作用 这种疾病 这里提出的研究将检查感觉神经肽 称为速激肽，可以作为炎症介质。 速激肽 包括神经肽P物质和神经激肽A，它们发挥它们的作用。 通过与神经激肽受体结合而起作用。 速激肽水平 P物质在哮喘肺中增加， 过敏原或臭氧暴露后的人类。 核心假设是 这里测试的是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中的关键介质 气道炎症 这一假设将通过使用转基因和 基因敲除技术来操纵感觉神经纤维的数量 它们支配着老鼠的肺。 炎症的发展，在 这些基因改变的小鼠在暴露于过敏原后的肺部， 臭氧或两种试剂的组合将通过以下方式测量： 组织学、生物化学和细胞学方法。 我们的假设 预测释放大量速激肽的小鼠 对过敏原和臭氧引起的气道炎症异常敏感， 释放出少量速激肽的小鼠会对这种药物产生抵抗力。 炎症的发展。 这些实验将允许 确定臭氧和过敏原是否协同作用以产生 炎症以及速激肽是否参与这些作用 试剂，单独或组合。 此外，分子 速激肽发挥其作用的途径将在 基因操控的老鼠 例如，神经激肽受体拮抗剂 将用于表征介导神经原性 小鼠的炎症，释放大量的速激肽。 分子生物学和生物化学方法也将用于确定 细胞因子mRNA和蛋白质产物的表达是否改变， 释放增加或减少量的速激肽的小鼠。 这本小说 采用基因操作小鼠的方法将提供有价值的 关于由速激肽诱导的炎症的机制信息， 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.