REGULATION OF NFKB IN LUNG EPITHELIUM BY ROS/RNS

ROS/RNS 对肺上皮中 NFKB 的调控

• 批准号: 2742050
• 负责人: Yvonne M. W. Janssen-Heininger
• 金额: $ 23.61万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2742050
• 关键词: apoptosis; cell line; confocal scanning microscopy; free radicals; gene expression; hydrogen peroxide; inflammation; lung injury; mitogen activated protein kinase; nuclear factor kappa beta; oxidative stress; peroxynitrites; respiratory epithelium; transfection

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.

活性氮（ROS/RNS）与肺组织的相互作用 上皮细胞是与吸入毒物接触的第一个细胞，可能是 在肺部疾病的发生中起关键作用。 激活 信号级联和转录因子可能是重要的 确定暴露于这些反应性物质的表型结果， 代谢物和炎症反应的激活。 在这 建议我们重点研究转录因子核因子κ B （NF-κ B）在大鼠肺泡II型上皮细胞系（RLE）中暴露于 ROS或RNS。 我们假设，NF-κ B的激活是由关键的 ROS/RNS通过独特的信号通路发生，包括促分裂原- 活化蛋白激酶（MAPK）和酪氨酸激酶， 这些事件的平衡在肺损伤的起始中是关键的。 NF-kappaB在多功能基因调控中起关键作用 参与炎症、免疫失调或生存。 通过NF-κ B阻止细胞凋亡可能会导致 炎症基因，氧化性肺损伤的标志。 由于其“ 复杂的功能，NF-κ B活化的表型意义 迄今为止，肺上皮细胞中存在的问题尚不清楚。 在本建议中，我们力求 研究ROS或RNS激活NF-κ B的机制， 关键信号通路和NF-的功能意义 RLE细胞中的kappaB活化。我们将调查两个关键的RNS， 过氧化氢，或过氧亚硝酸盐，以确定NF- kappaB活化和表型终点（细胞凋亡和 通过过度表达或过度表达调节NF-κ B， 阻止它的激活将使我们能够确定 ROS和RNS对肺上皮细胞NF-κ B活化的影响。此外，委员会认为， 上游信号级联和MAPK的评估以及 各种MAPKs的调节将阐明关键的信号传导 ROS/RNS诱导NF-κ B的途径。 综合办法， 具体目标1-4将导致更好地理解NF的作用， kappaB在与暴露于ROS/RNS相关的肺部疾病中的作用， 提供治疗干预的策略。