Mechanisms of ozone-induced pulmonary toxicity

描述（由申请人提供）：臭氧是一种普遍存在的城市空气污染物，已知会导致肺泡上皮损伤。对吸入臭氧的特征性肺反应是肺中活化的肺泡巨噬细胞和II型上皮细胞的数量增加。由这些细胞产生的各种介质，特别是活性氮中间体一氧化氮和过氧亚硝酸盐，可以促进组织损伤。一氧化氮是通过诱导型一氧化氮合酶（NOS 2）在细胞中产生的。热休克蛋白60（HSP 60）是一种被确定为臭氧诱导毒性的关键内源性介质的蛋白质。拟议的研究的总体目标是分析HSP 60在臭氧诱导的毒性中由肺泡巨噬细胞和II型细胞产生NOS2中的作用。我们的假设是，HSP 60有助于臭氧毒性，不仅通过诱导一氧化氮的产生，而且还通过刺激促炎细胞因子的释放，这些促炎细胞因子可以与HSP 60协同作用，在肺中产生过量的一氧化氮，从而导致组织损伤。

DESCRIPTION (provided by applicant): Ozone is a ubiquitous urban air pollutant known to cause alveolar epithelial injury. A characteristic pulmonary reaction to inhaled ozone is an increase in the number of activated alveolar macrophages and type II epithelial cells in the lung. A variety of mediators produced by these cells, in particular the reactive nitrogen intermediates nitric oxide and peroxynitrite, can contribute to tissue injury. Nitric oxide is generated in the cells via the inducible form of nitric oxide synthase (NOS2). One protein that has been identified as a key endogenous mediator of ozone-induced toxicity is heat shock protein 60 (HSP 60). The overall objectives of the proposed studies are to analyze the role of HSP 60 in the production of NOS2 by alveolar macrophages and type II cells in ozone-induced toxicity. Our hypothesis is that HSP 60 contributes to ozone toxicity, not just by inducing nitric oxide production, but also by stimulating the release of proinflammatory cytokines that can synergize with HSP 60 to generate excessive quantities of nitric oxide in the lung which contribute to tissue injury.