NITRIC OXIDE REGULATION OF ENDOTHELIAL IL-8 EXPRESSION

描述(改编自申请人的摘要)： 白介素8(IL-8)是一种由活化细胞分泌的致炎性多肽 内皮细胞。血管损伤经常是由过量引起的 肺损伤、创伤或缺血再灌注损伤时IL-8的分泌。 一氧化氮(NO)具有许多重要的生理作用，可以 在强烈内皮细胞条件下发挥抗炎作用 激活，但在其他情况下可能是促炎的，并促进 IL-8分泌。申请者进行的研究表明，没有人可以 对IL-8基因表达的不同调节作用取决于 内皮细胞的激活状态。这项提议的目的是 (1)确定NO在刺激特异性调控中的作用。 IL-8在体外激活的内皮细胞中的表达；(2)确定 小鼠IL-8诱导所必需的IL-8基因启动子区 静息内皮细胞；(3)鉴定参与转录的转录因子 介导NO对内皮细胞IL-8表达的影响；(4)使用 定点诱变以确定其身份和活性 启动子中具有无反应性的转录因子 构造。许多不同的分子技术将被用来 实现这些目标。仍有一个不完整的认识 NO对炎症的调节，但对NO治疗的人体试验 肺部的炎性损伤正在进行中。还有很多事情要做 了解一氧化氮在炎症过程中的作用。

DESCRIPTION (adapted from applicant's abstract): Interleukin-8 (IL-8) is a proinflammatory peptide secreted by activated endothelial cells. Vascular injury frequently results from excessive IL-8 secretion during spesis, trauma, or ischemia-reperfusion injury. Nitric oxide (NO), which has many important physiological roles, can serve an anti-inflammatory role under conditions of intense endothelial activation but may be proinflammatory under other conditions and promote IL-8 secretion. Research performed by the applicant suggests that NO may have different regulatory actions on IL-8 gene expression depending on the activation state of the endothelium. The aims of the proposal are (1) to characterize the role of NO in stimulus-specific regulation of IL-8 expression in activated in vitro endothelium; (2) to define promoter regions of the IL-8 gene necessary for IL-8 induction in resting endothelium; (3) to identify transcription factors involved in mediating NO's effects on endothelial IL-8 expression; and (4) to use site-directed mutagenesis to confirm identity and activity of transcription factors conferring NO-responsiveness in promoter constructs. A number of different molecular techniques will be used to accomplish these aims. There is still an incomplete understanding of NO's regulation of inflammation, yet human trials of NO therapy for inflammatory injury of the lung are under way. A great deal remains to be learned about NO's role in the inflammatory process.