REGULATION OF NFKB IN LUNG EPITHELIUM BY ROS/RNS

活性氮(ROS/RNS)与肺的相互作用 上皮细胞，第一个接触吸入毒物的细胞，可能是 在肺部疾病的始发过程中起关键作用。激活 信号级联和转录因子可能在 确定暴露于这些反应性物质的表型结果 代谢产物和炎症反应的激活。在这 建议我们专注于转录因子，核因子kappa B 核因子-kappaB在大鼠肺泡II型上皮细胞系中的表达 ROS或RNS。我们假设核因子-kappaB的激活是通过关键的 ROS/RNS通过独特的信号通路发生，其中包括有丝分裂原- 活化蛋白激酶(MAPK)和酪氨酸激酶，以及 这些事件的平衡在肺损伤的发生中起着关键作用。 核因子-kappaB在多种功能基因的调控中起关键作用 参与炎症、免疫失调或生存的疾病。 核因子-kappaB对细胞凋亡的抑制作用 炎症基因，氧化性肺损伤的标志。由于它的‘ 复杂功能，核因子-kappaB激活的表型意义 在肺上皮细胞中的表达至今尚不清楚。在这项建议中，我们寻求 研究ROS或RNS激活核因子-kappaB的机制 重要的信号转导途径及核因子-2的功能意义 RLE细胞中kappaB的激活。我们将调查两个关键的RN， 过氧化氢，或过氧亚硝酸盐，以确定核因子的含义- KappaB激活和表型终点(细胞凋亡和 炎症基因)。核因子-kappaB的调节 阻止它的激活将使我们能够确定其影响 ROS和RNS对肺上皮细胞核因子-kappaB活化的影响。此外， 评估上游信令级联和MAPK以及 对各种MAPK的调制将阐明关键的信号转导 ROS/RNS诱导核因子-kappaB的途径。在以下方面采用组合方法 具体目标1-4将有助于更好地理解核因子的作用- KappaB与暴露于ROS/RNS相关的肺部疾病，并可能 提供治疗干预的策略。

The interaction of reactive nitrogen species (ROS/RNS) with lung epithelium, the first cell in contact with inhaled toxicants, may be critical in the initiation of pulmonary disease. Activation of signalling cascades and transcription factors may be important in determining the phenotypic outcome of exposure to these reactive metabolites and the activation of an inflammatory response. In this proposal we focus on the transcription factor, nuclear factor kappa B (Nf-kappaB) in a rat alveolar type II epithelial cell line (RLE) exposed to ROS or RNS. We hypothesize that activation of NF-kappaB by critical ROS/RNS occurs through unique signalling pathways that include mitogen- activated protein kinases (MAPK) and tyrosine kinases, and that the balance of these events is pivotal in the initiation of lung injury. NF-kappaB is critical in the regulation of genes with multiple functions that are involved in inflammation, immune immodulation or survival. Prevention of apoptosis by NF-kappaB may lead to activation of inflammatory genes, a hallmark of oxidant lung injury. Due to its' complex functions, the phenotypic implications of NF-kappaB activation in lung epithelium are obscure to date. In this proposal, we seek to investigate the mechanisms by which ROS or RNS activate NF-kappaB, the critical signalling pathways and the functional implications of NF- kappaB activation in RLE cells. We will investigate two critical RNS, hydrogen peroxide, or peroxynitrite to determine the implications of NF- kappaB activation and phenotypic endpoints (apoptosis and expression of inflammatory genes).Modulation of NF-kappaB by overexpression or prevention of its activation will allow us to determine the implications of NF-kappaB activation in lung epithelium by ROS and RNS. Furthermore, assessment of upstream signalling cascades and MAPKs as well as the modulation of various MAPKs will elucidate the critical signalling pathways by which ROS/RNS induce NF-kappaB. Combined approaches in specific aims 1-4 will lead to a better understanding of the role of NF- kappaB in pulmonary disease associated with exposure to ROS/RNS and may provide strategies for therapeutic intervention.