Estrogen Protection of the Lung: Mechanisms and Pathways

雌激素对肺的保护：机制和途径

• 批准号: 6752409
• 负责人: SAMI I SAID
• 金额: $ 25.2万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752409
• 关键词: biological signal transduction; cellular pathology; chemical structure function; cytoprotection; cytotoxicity; disease /disorder model; estrogen receptors; estrogens; excitatory aminoacid; gene environment interaction; gene expression; genetically modified animals; hamsters; hormone regulation /control mechanism; intermolecular interaction; laboratory mouse; laboratory rat; lung injury; microarray technology; model design /development; oxidative stress; paraquat; pulmonary edema; respiratory toxin

DESCRIPTION (provided by applicant): The broad objectives of this proposal are: to achieve better means of cell and tissue protection, and to gain a better understanding of cell-protective actions and functions of the female sex hormone estrogen. Specifically and near-term, we propose to examine the ability of estrogen to protect against certain forms of acute lung injury, and the mechanisms of this action. Specific objectives: 1) Document the protective properties of estrogen hormone against acute lung injury. Hypothesis: Already shown to be cytoprotective in neuronal cells and the cardiovascular system, estrogen is protective in the lung as well. This hypothesis will be tested in three models of injury: a) excitotoxicity, i.e., injury/cell death due to species overstimulation of NMDA receptors; b) oxidative stress, caused by the generation of reactive oxygen species (ROS) by the herbicide paraquat; and c) endotoxin shock, which leads to multi-organ dysfunction. Endpoints will be the speed of onset and the severity of high-permeability pulmonary edema in models a and b, and the survival time and organ damage, in model c. 2) Explore the mechanisms, sites, and pathways of lung protection by estrogen. Hypothesis: Acting at multiple sites, estrogen exerts anti-apoptotic (pro-survival), anti-inflammatory, anti-oxidant, and other beneficial effects. These possible sites and models of protection will be examined in the models of injury named above. We will evaluate: a) the specificity and nature of the effect (i.e., genomic vs. nongenomic); b) relative importance of different receptors (ER-alpha, ER-beta), membrane binding sites, and transduction pathways; c) the contribution of estrogen-induced upregulation of the expression of (VIP), which has known anti-injury and anti-inflammatory properties; d) possible interactions and "transcription cross-talk" between estrogen and retinoic acid receptors, and d) anti-apoptotic and pro-survival activities of estrogen. The proposed work extends recent research on the protective effects of estrogen in the brain and the cardiovascular system. Preliminary data support the validity of the hypotheses underlying this project. This is the first, and probably the only, investigation of the female sex hormone estrogen as a lung-protective agent.

描述（由申请人提供）：该提案的主要目标是： 获得更好的细胞和组织保护手段，并获得更好的效果 了解女性的细胞保护作用和功能 激素雌激素。具体而言，近期，我们建议检查能力 雌激素可预防某些形式的急性肺损伤，以及 这一行动的机制。具体目标： 1) 记录保护措施 雌激素对抗急性肺损伤的特性。假设：已经 显示对神经细胞和心血管系统具有细胞保护作用， 雌激素对肺部也有保护作用。该假设将在 三种损伤模型：a) 兴奋性毒性，即由于以下原因导致的损伤/细胞死亡 物种过度刺激 NMDA 受体； b) 氧化应激，由 除草剂百草枯产生活性氧（ROS）；和c) 内毒素休克，导致多器官功能障碍。端点将是 模型中高渗透性肺水肿的发生速度和严重程度 a 和 b，以及模型 c 中的生存时间和器官损伤。 2）探索 雌激素保护肺的机制、位点和途径。假设： 雌激素在多个部位发挥作用，具有抗细胞凋亡（促存活）、 抗炎、抗氧化和其他有益作用。这些可能 保护部位和模型将在名为“损伤模型”的损伤模型中进行检查 多于。我们将评估： a) 效果的特异性和性质（即， 基因组与非基因组）； b) 不同受体的相对重要性 （ER-α、ER-β）、膜结合位点和转导途径； c) 的 雌激素诱导的 (VIP) 表达上调的贡献，其中 具有已知的抗损伤和抗炎特性； d) 可能的 雌激素和视黄酸之间的相互作用和“转录串扰” 受体，以及 d) 雌激素的抗凋亡和促生存活性。这 拟议的工作扩展了近期关于雌激素保护作用的研究 大脑和心血管系统。初步数据支持有效性 该项目的假设。这是第一个，也可能是第一个 仅对女性性激素雌激素作为肺保护作用的研究 代理人。