THE EFFECTS OF ENDOTHELIN ON ENOTIN-INDUCED PULMONARY VASCULAR IACM-1 EXPRESSION AND ITS APPLICATION TO THE THERAPEUTIC STRATEGY OF ACUTE LUNG INJURY

内皮素-1 （ET-1）和一氧化氮（NO）在肺血管张力的控制中起相反的作用。近年来，这些血管活性物质被认为是局部血管内皮细胞的稳态调节剂。在炎症部位，血管内皮细胞被激活，内皮细胞表面的内皮-白细胞粘附分子如细胞间粘附分子-1 （ICAM-1）上调。在本项目中，我们检测了ET-1和NO对培养的人肺微血管内皮细胞（HPMVEC）中ICAM-1表达的影响。结果总结如下：1。未刺激状态下，ET-1和NO均未影响hpmvec细胞中ICAM-1的表达。通过细胞表面酶免疫测定，NO以剂量依赖的方式抑制内毒素（LPS）刺激的ICAM-1表达，抑制率为30-50%。相反，ET-1对lps刺激的ICAM-1表达无影响。免疫荧光研究表明，NO抑制ICAM-1表达的机制部分与抑制跨核定位转录核因子- cb （NF-κB）有关。最近有几条证据表明NO具有抗白细胞自身样细胞的作用。我们目前的研究提供了一氧化氮和白细胞之间的联系，并为这种作用的机制提供了线索。我们推测针对NF-κB的调节策略的发展可能为治疗肺部炎症性疾病提供新的治疗工具。

Endothelin-1 (ET-1) and Nitric Oxide (NO) play an opposing role in the control of pulmonary vascular tone. Recently, these vasoactive substances have recognized as homeostatic regulator of local vascular endothelial cells. At the site of inflammation, vascular endothelial cells are activated and endothelial-leukocyte adhesion molecules such as intercellular adhesion molecule-l (ICAM-1) are up regulated on the surface of endothelial cells.In this project, we examined the impact of ET-1 and NO on ICAM-1 expression on cultured human pulmonary microvascular endothelial cells (HPMVEC). The results are summarized as below:1. Under unstimulated state, neither ET-1 nor NO had any effects on ICAM-1 expression on HPMVEC.2. NO inhibited endotoxin (LPS)-stimulated ICAM-1 expression in a dose dependent manner by 30-50% as determined by cell surface enzyme immunoassays. In contrast, ET-1 had no effect on LPS-stimulated ICAM-1 expression.3. Immunofluorescence study indicates that the mechanism by which NO inhibits ICAM-1 expression, in part, involves inhibition of transnuclear location transcriptional nuclear factor-CB (NF-κB).Several lines of evidence have recently suggested a role for NO as an antileukocyte autacoid. Our present study provides a link between NO and leukocyte and offers clues as to the mechanism of such an effect. We speculate development of modulatory strategies targeting NF-κB my provide a novel therapeutic tool for the treatment of lung inflammatory disease.