LUNG SURFACE ANTIOXIDANT DEFENSES AGAINST AIR POLLUTANTS

描述(改编自申请人的摘要)：呼吸道 通常暴露在各种氧化性空气污染物中，如臭氧， 二氧化氮或香烟烟雾，可引起炎症反应 在呼吸道，并导致肺损伤。因为它的高度 反应性，吸入的臭氧预计主要与呼吸相互作用 肠道衬里液体(RTLF)，第一个进入的生物基质 接触吸入污染物。RTLF包含大量的 低分子质量抗氧化剂(抗坏血酸、尿酸、谷胱甘肽和 A-生育酚)，它可以用来保护 这些RTLF(如表面活性物质)以及来自 吸入空气污染物造成的直接氧化损伤。然而，消息来源和 这些RTLF抗氧化剂的实际浓度尚不清楚。这个 申请人假设呼吸道上皮细胞对 维持RTLF低分子质量的抗氧化剂，并可能参与 抗氧化剂回收。第一个目标将从不同的角度分析实时荧光 呼吸道中这些低分子质量抗氧化剂的区域， 通过使用不同的鼻腔和支气管收集人类志愿者的RTLF 灌洗技术。第二个目标将描述 呼吸道上皮可能有助于维持细胞外 使用培养的支气管和肺泡的抗氧化剂水平 上皮细胞，并将研究这种机制在 对吸入氧化剂如臭氧造成的上皮损伤的防御。一个 重要的RTLF组件，特别是在呼吸道炎症期间， 是一种一氧化氮，众所周知，它很容易与臭氧反应。因此，毒性 由于臭氧吸入可能受到NO增加的调节 制作。NO或其代谢物亚硝酸盐与臭氧的反应可能有助于 作为防止臭氧伤害的一种保护机制，但可能导致 对臭氧有贡献的活性氮物种(NO2或ONOO-) 毒性。第三个目标是调查这些可能性。最后，由于 臭氧所致的肺损伤很可能是通过与 导致二次氧化剂形成的RTLF成分，第四 AIM将用RTLF成分表征反应产物，试图 识别次生毒物或具有特征的氧化产物 可作为体内臭氧暴露的“剂量计”。此信息是 可能会增加我们对吸入空气造成的肺损伤的了解 污染物，并将有助于制定预防肺损伤的战略 通过吸入氧化剂。

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.