Anti-inflammatory actions of lipoxin A4 stable analogs are demonstrable in human whole blood:: Modulation of leukocyte adhesion molecules and inhibition of neutrophil-endothelial interactions
Anti-inflammatory actions of lipoxin A4 stable analogs are demonstrable in human whole blood:: Modulation of leukocyte adhesion molecules and inhibition of neutrophil-endothelial interactions
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DOI：
10.1182/blood.v94.12.4132.424k25_4132_4142
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发表时间：
1999-12-15
期刊：
影响因子：
20.3
通讯作者：
Serhan, CN
中科院分区：
文献类型：
--
作者：
Filep, JG;Zouki, C;Serhan, CN
我们在全血中检测了2脂素A(4) （LXA(4)）稳定类似物，15-R/ s -甲基-LXA(4)和16-苯氧基-LXA(4)，它们对体外人白细胞和冠状动脉内皮细胞（HCAEC）粘附分子表达的影响，以及对中性粒细胞对HCAEC粘附的影响。两种浓度为纳摩尔至微摩尔的LXA4类似物均可阻止l -选择素的脱落，并下调静息中性粒细胞、单核细胞和淋巴细胞中CD11/CD18的表达。LXA(4)类似物还能减弱血小板活化因子（PAF）、白介素-8或c反应蛋白衍生肽201-206引起的L-选择素和CD11/CD18表达的变化，IC50值为0.2 ~ 1.9 μ mol/L。然而，它们不影响脂多糖（LPS）或肿瘤坏死因子α刺激的e-选择素和细胞间粘附分子-1在HCAEC上的表达。这些LXA(4)类似物显著降低中性粒细胞对lps活化的HCAEC的粘附。粘附抑制作用与功能阻断型抗e -选择素和抗l-选择素抗体有叠加作用，与抗cd18抗体无叠加作用。LXA(4)类似物与地塞米松（100 nmol/L）联合使用几乎完全抑制paf诱导的白细胞粘附分子表达变化，并对中性粒细胞粘附HCAEC具有加性抑制作用。用地塞米松培养HCAEC，而不使用LXA4类似物，也减少了中性粒细胞的附着。综上所述，这些结果表明LXA4稳定类似物调节l -选择素和CD11/CD18在静息和免疫刺激的白细胞上的表达，并通过降低CD11/CD18的表达来抑制中性粒细胞对HCAEC的粘附。这些作用与糖皮质激素的作用是叠加的，可能代表了LXA4和阿司匹林触发的15-epi-LXA(4)调节白细胞运输的一种新的有效调节机制。(C) 1999年由美国血液病学会出版。
We have examined in whole blood the actions of 2 lipoxin A(4) (LXA(4)) stable analogs, 15-R/S-methyl-LXA(4) and 16-phenoxy-LXA(4), for their impact on the expression of adhesion molecules on human leukocytes and coronary artery endothelial cells (HCAEC) and on neutrophil adhesion to HCAEC in vitro. Both LXA4 analogs in nanomolar to micromolar concentrations prevented shedding of L-selectin and downregulated CD11/CD18 expression on resting neutrophils, monocytes, and lymphocytes. Changes in CD11/CD18 expression were blocked by the mitogen-activated protein kinase kinase inhibitor PD98059, The LXA(4) analogs also attenuated changes in L-selectin and CD11/CD18 expression evoked by platelet-activating factor (PAF), interleukin-8, or C-reactive protein-derived peptide 201-206 with IC50 values of 0.2 to 1.9 mu mol/L, whereas they did not affect lipopolysaccharide (LPS)- or tumor necrosis factor-alpha-stimulated expression of E-selectin and intercellular adhesion molecule-1 on HCAEC. These LXA(4) analogs markedly diminished adhesion of neutrophils to LPS-activated HCAEC. Inhibition of adhesion was additive with function blocking anti-E-selectin and anti-l-selectin antibodies, but was not additive with anti-CD18 antibody. Combining LXA(4) analogs with dexamethasone (100 nmol/L) almost completely inhibited PAF-induced changes in adhesion molecule expression on leukocytes and gave additive inhibition of neutrophil adhesion to HCAEC. Culture of HCAEC with dexamethasone, but not with LXA4 analogs, also decreased neutrophil attachment. Together, these results indicate that LXA4 stable analogs modulate expression of both L-selectin and CD11/CD18 on resting and immunostimulated leukocytes and inhibit neutrophil adhesion to HCAEC by attenuating CD11/CD18 expression. These actions are additive with those of glucocorticoids and may represent a novel and potent regulatory mechanism by which LXA4 and aspirin-triggered 15-epi-LXA(4) modulate leukocyte trafficking. (C) 1999 by The American Society of Hematology.