Hofman F M, Chen P, Jeyaseelan R, Incardona F, Fisher M, Zidovetzki R
Departments of Pathology, Medicine, and Neurology, University of Southern California, Los Angeles; and the Departments of Biology and Neuroscience, University of California, Riverside, CA, USA.
Blood. 1998 Nov 1;92(9):3064-72.
Increased levels of endothelin-1 (Et-1), a potent vasoconstrictor, have been correlated with hypertension and neuronal damage in ischemic/reperfusion injury. The presence of polymorphonuclear cells (PMNs) in the brain has been shown to be directly responsible for this observed pathology. To address the question of whether Et-1 plays a role in this process, human brain-derived endothelial cells (CNS-ECs) were cultured with Et-1. The results demonstrate that Et-1 induces production of the neutrophil chemoattractant interleukin-8 (IL-8) twofold to threefold after 72 hours; mRNA was maximal after 1 hour of stimulation. Conditioned culture medium derived from Et-1-stimulated CNS-ECs induced a chemotactic response in the PMN migration assay. The inflammatory cytokines tumor necrosis factor-alpha (TNF) and IL-1beta functioned additively with Et-1 in increasing IL-8 production. In contrast, transforming growth factor-beta (TGF-beta), but not IL-10, completely abolished the effect of Et-1 on IL-8 production. However, Et-1 did not modulate intercellular adhesion molecule-1 (ICAM-1) expression. These data demonstrate that Et-1 may be a risk factor in ischemic/reperfusion injury by inducing increased levels of the neutrophil chemoattractant IL-8.
内皮素-1（Et-1）是一种强效血管收缩剂，其水平升高与缺血/再灌注损伤中的高血压和神经元损伤相关。已证明大脑中多形核细胞（PMN）的存在是这种观察到的病理变化的直接原因。为了解决Et-1是否在此过程中起作用的问题，将人脑来源的内皮细胞（CNS-ECs）与Et-1一起培养。结果表明，72小时后Et-1诱导中性粒细胞趋化因子白细胞介素-8（IL-8）的产生增加两倍至三倍；刺激1小时后mRNA达到最大值。在PMN迁移试验中，来自Et-1刺激的CNS-ECs的条件培养基诱导了趋化反应。炎症细胞因子肿瘤坏死因子-α（TNF）和IL-1β与Et-1协同作用增加IL-8的产生。相反，转化生长因子-β（TGF-β）而非IL-10完全消除了Et-1对IL-8产生的影响。然而，Et-1并未调节细胞间黏附分子-1（ICAM-1）的表达。这些数据表明，Et-1可能通过诱导中性粒细胞趋化因子IL-8水平升高而成为缺血/再灌注损伤的一个危险因素。
