THE ANTIINFLAMMATORY MECHANISM OF METHOTREXATE - INCREASED ADENOSINE RELEASE AT INFLAMED SITES DIMINISHES LEUKOCYTE ACCUMULATION IN AN IN-VIVO MODEL OF INFLAMMATION
THE ANTIINFLAMMATORY MECHANISM OF METHOTREXATE - INCREASED ADENOSINE RELEASE AT INFLAMED SITES DIMINISHES LEUKOCYTE ACCUMULATION IN AN IN-VIVO MODEL OF INFLAMMATION
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DOI：
10.1172/jci116884
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发表时间：
1993-12-01
影响因子：
15.9
通讯作者：
OSTAD, E
中科院分区：
文献类型：
--
作者：
CRONSTEIN, BN;NAIME, D;OSTAD, E
甲氨蝶呤，叶酸拮抗剂，是一个有效的抗炎剂，每周使用低浓度。我们检验了甲氨蝶呤的抗炎作用是由于它能够促进细胞内5-氨基咪唑-4-羧基酰胺核糖核苷酸（AICAR）的积累，在细胞损伤的条件下，增加局部腺苷的释放。我们现在提出了第一个证据，在体内炎症模型中建立这种作用机制，即小鼠气袋模型。小鼠在诱导气囊期间腹腔注射甲氨蝶呤或生理盐水3-4周。药理学上相关剂量的甲氨蝶呤增加了脾细胞AICAR含量，提高了卡拉胶炎症气袋渗出液中腺苷的浓度，并显著抑制了炎症气袋中白细胞的积聚。通过将腺苷脱氨酶（ADA）注射到气囊中，甲氨蝶呤介导的白细胞积累减少被部分逆转，被特异性腺苷a受体拮抗剂3,7-二甲基-1-丙基黄嘌呤（DMPX）完全逆转，但不受腺苷Al受体拮抗剂8-环戊基-二丙基黄嘌呤的影响。用生理盐水或强抗炎类固醇地塞米松治疗的动物，ADA和DMPX均不影响炎症眼袋中的白细胞积累。这些结果表明甲氨蝶呤是一种非甾体抗炎剂，其抗炎作用是由于在炎症部位增加腺苷释放。
Methotrexate, a folate antagonist, is a potent antiinflammatory agent when used weekly in low concentrations. We examined the hypothesis that the antiphlogistic effects of methotrexate result from its capacity to promote intracellular accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) that, under conditions of cell injury, increases local adenosine release. We now present the first evidence to establish this mechanism of action in an in vivo model of inflammation, the murine air pouch model. Mice were injected intraperitoneally with either methotrexate or saline for 3-4 wk during induction of air pouches. Pharmacologically relevant doses of methotrexate increased splenocyte AICAR content, raised adenosine concentrations in exudates from carrageenan-inflamed air pouches, and markedly inhibited leukocyte accumulation in inflamed air pouches. The methotrexate-mediated reduction in leukocyte accumulation was partially reversed by injection of adenosine deaminase (ADA) into the air pouch, completely reversed by a specific adenosine A, receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), but not affected by an adenosine Al receptor antagonist, 8-cyclopentyl-dipropylxanthine. Neither ADA nor DMPX affected leukocyte accumulation in the inflamed pouches of animals treated with either saline or the potent antiinflammatory steroid dexamethasone. These results indicate that methotrexate is a nonsteroidal antiinflammatory agent, the antiphlogistic action of which is due to increased adenosine release at inflamed sites.