NITRIC OXIDE REGULATION OF ENDOTHELIAL IL-8 EXPRESSION

描述（改编自申请人摘要）： 白细胞介素-8（IL-8）是由活化的白细胞介素-8（IL-8）分泌的促炎肽。 内皮细胞血管损伤通常是由于过度的 IL-8分泌在spesis，创伤，或缺血再灌注损伤。 一氧化氮（NO）具有许多重要的生理作用， 在强烈的内皮细胞增生的情况下， 激活，但在其他条件下可能是促炎性的，并促进 IL-8分泌。申请人进行的研究表明，NO可能 对IL-8基因表达有不同的调节作用， 内皮的激活状态。该提案的目的是 (1)表征NO在刺激特异性调节中的作用， IL-8在体外活化内皮细胞中的表达;（2）确定 IL-8诱导所必需的IL-8基因的启动子区， 静息内皮细胞;（3）确定参与 介导NO对内皮细胞IL-8表达的影响;以及（4）使用 定点诱变以确认 启动子中赋予NO反应性的转录因子 结构。许多不同的分子技术将被用于 实现这些目标。人们仍然不完全了解 NO对炎症的调节，但NO治疗的人体试验 肺部的炎性损伤正在发生。仍有大量工作要 了解NO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.