Inhibition of leukotriene B4 synthesis in neutrophils from patients with rheumatoid arthritis by a single oral dose of methotrexate.
Inhibition of leukotriene B4 synthesis in neutrophils from patients with rheumatoid arthritis by a single oral dose of methotrexate.
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DOI：
10.1002/art.1780330815
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发表时间：
2010-08
影响因子：
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通讯作者：
R. Sperling;J. Coblyn;J. Larkin;A. I. Benincaso;K. Austen;M. Weinblatt
中科院分区：
文献类型：
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作者：
R. Sperling;J. Coblyn;J. Larkin;A. I. Benincaso;K. Austen;M. Weinblatt
我们研究了一个单一的，口服剂量的甲氨蝶呤（MTX）对花生四烯酸代谢的中性粒细胞从6例类风湿性关节炎，这是1天前和1天后，他们通常每周MTX剂量。6例患者接受了平均每周9.6 mg MTX剂量（范围5-15），平均61.7个月（范围58-64），无患者接受伴随皮质类固醇。在用10 μ M钙离子载体A23187离体刺激20分钟的中性粒细胞中，与给药前水平相比，MTX给药后，白三烯B4（LTB 4）的总生成被显著抑制，平均抑制53（平均值+/- SEM 13.0 +/- 1.4 ng/10（6）个细胞对6.0 +/- 0.9 ng/10（6）个细胞; P = 0.0019），反映了释放的和细胞保留的LTB 4的相当的抑制。LTB 4的ω-氧化产物减少49%表明，LTB 4合成减少而不是降解增加是导致LTB 4生成减少的原因。没有一个显着的变化，无论是3 H-标记的花生四烯酸释放或血小板活化因子的产生表明，观察到的LTB 4合成减少显然不是由磷脂酶A2活性降低引起的。MTX给药后，5-脂氧合酶产物5-羟基二十碳四烯酸和6-反式-LTB 4非对映异构体的总形成减少28%，LTB 4及其ω-氧化代谢物的产生抑制48%，表明5-脂氧合酶活性受到抑制，并可能抑制白三烯A4环氧化物水解酶活性。
We studied the effects of a single, oral dose of methotrexate (MTX) on arachidonic acid metabolism in neutrophils from 6 patients with rheumatoid arthritis, which were obtained 1 day before and 1 day after their usual weekly MTX dose. The 6 patients had received a mean weekly MTX dose of 9.6 mg (range 5-15) for a mean of 61.7 months (range 58-64), and none received concomitant corticosteroids. Total generation of leukotriene B4 (LTB4) in neutrophils stimulated ex vivo with 10 microM calcium ionophore A23187 for 20 minutes was significantly suppressed, by a mean of 53%, after the MTX dose compared with the predose levels (mean +/- SEM 13.0 +/- 1.4 ng/10(6) cells versus 6.0 +/- 0.9 ng/10(6) cells; P = 0.0019), reflecting a comparable suppression of both released and cell-retained LTB4. A 49% decrease in omega-oxidation products of LTB4 demonstrates that decreased LTB4 synthesis, rather than increased degradation, is responsible for the decrease in LTB4 generation. The absence of a significant change in either 3H-labeled arachidonic acid release or platelet-activating factor generation indicates that the observed decrease in LTB4 synthesis was apparently not caused by diminished phospholipase A2 activity. A 28% decrease in the total formation of the 5-lipoxygenase products 5-hydroxyeicosatetraenoic acid and the 6-trans-LTB4 diastereoisomers, and a 48% suppression of production of LTB4 plus its omega-oxidation metabolites after the MTX dose suggest inhibition of 5-lipoxygenase activity and possible suppression of leukotriene A4 epoxide hydrolase activity.