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)在控制肺血管张力中起着相反的作用。近年来，这些血管活性物质已被公认为局部血管内皮细胞的动态平衡调节剂。在炎症部位，血管内皮细胞被激活，内皮细胞表面的细胞间黏附分子-L(ICAM-1)等内皮-白细胞黏附分子表达上调。结果如下：1.在非刺激状态下，ET-1和NO对HPMVEC.2细胞ICAM-1的表达均无影响。细胞表面酶免疫分析显示，NO以剂量依赖的方式抑制内毒素(LPS)刺激的ICAM-1的表达30-50%。相反，ET-1对内毒素刺激的ICAM-1表达无影响。免疫荧光研究表明，NO抑制细胞间黏附分子-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。最近的一些证据表明，NO作为一种抗白细胞金丝桃体具有作用。我们目前的研究提供了NO与白细胞之间的联系，并为这种作用的机制提供了线索。我们推测针对NF-κB的调控策略的发展可能为肺部炎症性疾病的治疗提供一种新的治疗工具。

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.