Superoxide anion mediates the L-selectin down-regulation induced by non-steroidal anti-inflammatory drugs in human neutrophils
Superoxide anion mediates the L-selectin down-regulation induced by non-steroidal anti-inflammatory drugs in human neutrophils
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DOI：
10.1016/j.bcp.2012.10.024
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发表时间：
2013-01-15
影响因子：
5.8
通讯作者：
Diaz-Gonzalez, Federico
中科院分区：
文献类型：
--
作者：
Dominguez-Luis, Maria;Herrera-Garcia, Ada;Diaz-Gonzalez, Federico
非甾体抗炎药(NSAIDs)通过一种尚不清楚的机制诱导人中性粒细胞L选择素的脱落。在这项工作中，我们研究了非甾体抗炎药在中性粒细胞/内皮细胞动态相互作用中的功能作用，以及活性氧自由基(ROS)在非甾体抗炎药介导的L-选择素下调中的潜在参与。当人的中性粒细胞与双氯芬酸孵育时，观察到在活化的内皮细胞上滚动的细胞数量显著减少。不同的非甾体抗炎药(氟芬酸、甲氯芬酸、双氯芬酸、消炎痛、尼美舒利、氟比洛芬、美洛昔康、苯丁酮、吡罗昔康、酮洛芬和阿司匹林)均可引起中性粒细胞内ROS浓度不同程度的升高，且与L-选择素表面表达的变化成反比。中性粒细胞预先与超氧化物歧化酶共同孵育，但不与过氧化氢酶共同孵育，对几种非甾体抗炎药引起的L-选择素下调有明显的保护作用，而双氯芬酸对中性粒细胞滚动的影响明显减弱。有趣的是，双氯芬酸和氟芬酸可显著增加中性粒细胞胞外超氧阴离子的产生，但吡罗昔康对其无明显影响，而用二苯碘抑制烟酰胺腺嘌呤二核苷酸磷酸酶的活性可阻止双氯芬酸对L选择素的下调。根据这些结果，慢性肉芽肿性疾病患者中性粒细胞形成超氧阴离子自由基的能力降低，与正常对照组(IC50：5.6mU/ml)相比，慢性肉芽肿性疾病患者中性粒细胞对L-选择素的下调(IC_(50)：15.3mU/ml)更低。结论：一组非甾体抗炎药通过依赖NADPH氧化酶在质膜产生超氧阴离子而触发L-选择素脱落，从而干扰中性粒细胞与内皮细胞的相互作用。(C)2012 Elsevier Inc.保留所有权利。
Non-steroidal anti-inflammatory drugs (NSAIDs) induce the shedding of L-selectin in human neutrophils through a mechanism still not well understood. In this work we studied both the functional effect of NSAIDs on the neutrophils/endothelial cells dynamic interaction, and the potential involvement of reactive oxygen species (ROS) in the NSAIDs-mediated down-regulation of L-selectin. When human neutrophils were incubated with diclofenac, a significant reduction in the number of cells that rolled on activated endothelial cells was observed. Different NSAIDs (flufenamic acid, meclofenamic acid, diclofenac, indomethacin, nimesulide, flurbiprofen, meloxicam, phenylbutazone, piroxicam, ketoprofen and aspirin) caused variable increase in neutrophil intracellular ROS concentration, which was inversely proportional to the change produced in L-selectin surface expression. Pre-incubation of neutrophils with superoxide dismutase, but not with catalase, showed both a significant protective effect on the L-selectin down-regulation induced by several NSAIDs and a diminished effect of diclofenac on neutrophil rolling. Interestingly, diclofenac and flufenamic acid but not piroxicam significantly increased the extracellular superoxide anion production by neutrophils, and inhibition of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase activity with diphenyleneiodonium prevented the down-regulation of L-selectin by diclofenac. In accordance with these results, neutrophils from patients with chronic granulomatous disease, a hereditary disease in which neutrophils show a reduced capacity to form superoxide radicals, exhibited a lower down-regulation of L-selectin (IC50: 15.3 mu g/ml) compared to normal controls (IC50: 5.6 mu g/ml) in response to diclofenac.Conclusion: A group of NSAIDs is capable of interfering with the ability of neutrophils to interact with endothelial cells by triggering L-selectin-shedding through the NADPH-oxidase-dependent generation of superoxide anion at the plasma membrane. (C) 2012 Elsevier Inc. All rights reserved.