LUNG SURFACE ANTIOXIDANT DEFENSES AGAINST AIR POLLUTANTS

描述（改编自申请人摘要）：呼吸道 通常暴露在各种氧化性空气污染物中，例如臭氧， 二氧化氮或香烟烟雾，可诱导炎症反应 在呼吸道中，并导致肺损伤。 由于其高 反应性，吸入臭氧预计主要与呼吸道相互作用， 道衬液（RTLFs），第一个生物基质进入 接触吸入的污染物。 RTLF包含大量的 低分子量抗氧化剂（抗坏血酸盐、尿酸盐、谷胱甘肽（GSH）和 α-生育酚），其可用于保护 这些RTLF（例如表面活性剂）以及来自 吸入空气污染物的直接氧化损伤。 然而，来源和 这些RTLF抗氧化剂的实际浓度尚不清楚。 的 申请人假设呼吸道上皮细胞有助于 维持RTLF低分子量抗氧化剂，并可能参与 抗氧化剂回收 第一个目标将分析RTLF从各种 这些低分子量抗氧化剂的呼吸道区域， 通过使用不同的鼻和支气管从人类志愿者收集RTLF， 灌洗技术。 第二个目标将描述各种机制的特点， 呼吸道上皮可能有助于维持细胞外 抗氧化剂水平，使用培养的支气管和肺泡 上皮细胞，并将研究这种机制的重要性， 防止吸入的氧化剂如臭氧对上皮细胞的损伤。 一个 重要RTLF成分，特别是在呼吸道炎症期间， 是一氧化氮，已知其容易与臭氧反应。 因此，毒性 由于吸入臭氧，可能会受到NO增加的调节 生产 NO或其代谢物亚硝酸盐与臭氧的反应可能有助于 作为防止臭氧损伤的保护机制，但可能导致形成 活性氮物质（NO2或ONOO-），可促进臭氧 毒性 第三个目标是研究这些可能性。 最后作为 臭氧引起的肺损伤最有可能是通过初始反应介导的 RTLF成分导致形成二次氧化剂，第四次氧化剂 aim将用RTLF组分表征反应产物， 以确定次级毒物或特征氧化产物， 可用作体内暴露于臭氧的“剂量计”。 该信息 可能会增加我们对吸入空气引起的肺损伤的了解 污染物，并将能够制定预防肺损伤的战略 吸入的氧化剂

DESCRIPTION (Adapted from the applicant's abstract): The respiratory tract is commonly exposed to a variety of oxidizing air pollutants, such as ozone, nitrogen dioxide or cigarette smoke, which can induce inflammatory responses in the respiratory tract, and result in lung injury. Because of its high reactivity, inhaled ozone is expected to interact primarily with respiratory tract lining fluids (RTLFs), the first biological matrix to come into contact with inhaled pollutants. The RTLFs contain significant amounts of low-molecular mass antioxidants (ascorbate, urate, glutathione (GSH) and a-tocopherol), that may serve to protect functional constituents within these RTLFs (e.g. surfactant) as well as the underlying epithelium from direct oxidative injury by inhaled air pollutants. However, the sources and actual concentrations of these RTLF antioxidants are not clear. The applicant hypothesizes that respiratory tract epithelial cells contribute to maintain RTLF low-molecular mass antioxidants and may be involved in antioxidant recycling. The first aim will analyze RTLFs from various regions of the respiratory tract for these low-molecular mass antioxidants, by collecting RTLFs from human volunteers using various nasal and bronchial lavage techniques. The second aim will characterize mechanisms by which the respiratory tract epithelium may contribute to maintain extracellular antioxidant levels, with the use of cultured bronchial and alveolar epithelial cells, and will investigate the importance of such mechanisms in the defense against epithelial injury by inhaled oxidants such as ozone. An important RTLF component, especially during respiratory tract inflammation, is nitric oxide which is known to react readily with ozone. Hence, toxicity due to ozone inhalation is likely to be modulated by increased NO production. Reaction of NO, or its metabolite nitrite, with ozone may serve as a protective mechanism against ozone injury, but may result in formation of reactive nitrogen species (NO2 or ONOO-) that can contribute to ozone toxicity. The third aim is to investigate these possibilities. Finally, as ozone induced lung injury is most likely mediated via initial reaction with RTLF constituents resulting in formation of secondary oxidants, the fourth aim will characterize reaction products with RTLF components, in an attempt to identify secondary toxicants or characteristic oxidation products that can serve as "dosimeters" of in vivo exposure to ozone. This information is likely to increase our understanding of lung injury due to inhalation of air pollutants, and will enable development of strategies to prevent lung injury by inhaled oxidants.