Comparative study of glucocorticoids, cyclosporine A, and JTE-607[(-)-ethyl-N-{3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl}-L-phenylalaninate dihydrochloride] in a mouse septic shock model
Comparative study of glucocorticoids, cyclosporine A, and JTE-607[(-)-ethyl-N-{3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl}-L-phenylalaninate dihydrochloride] in a mouse septic shock model
复制标题
DOI：
10.1124/jpet.104.072421
复制
发表时间：
2004-12-01
影响因子：
3.5
通讯作者：
Wakitani, K
中科院分区：
文献类型：
--
作者：
Iwamura, H;Sato, M;Wakitani, K
糖皮质激素、环孢素 A 和 JTE-607 [(-)乙基-N-{3,5-二氯-2-羟基-4-[2-(4-甲基哌嗪-1-基)乙氧基]苯甲酰基}-L-苯丙氨酸二盐酸盐]（一种不抑制白介素 (IL)-2 或干扰素-γ 的促炎细胞因子抑制剂）在小鼠败血性休克中的作用进行了比较盲肠结扎穿刺（CLP）诱导模型。 CLP引起肺中巨噬细胞炎症蛋白(MIP)-2以及血浆和腹腔液中MIP-2和IL-6的升高，在CLP后4至8小时达到峰值。 CLP 后 8 至 12 小时，肺中的髓过氧化物酶 (MPO) 活性增加并达到峰值。用 JTE-607 和甲基强的松龙对小鼠进行急性治疗（CLP 前 1 小时和后 2 小时皮下注射）显示出对细胞因子水平和 MPO 活性升高的显着抑制，并提高了存活率。用环孢素A和泼尼松龙进行类似治疗无效。对小鼠进行慢性治疗（CLP 前连续 7 天皮下注射）JTE-607 也显示出对细胞因子产生、MPO 活性和死亡率的抑制作用。相比之下，环孢素 A 和泼尼松龙的长期治疗不会抑制细胞因子的产生或 MPO 活性，反而会加剧死亡率。这些结果表明，JTE-607 对 CLP 诱导的小鼠死亡率具有保护作用，与促炎细胞因子的抑制相关，而免疫抑制剂环孢素 A 和泼尼松龙则没有。这表明 JTE-607 作为一种不会引起不良免疫抑制的多重细胞因子抑制剂，可用于治疗感染性休克。
Actions of glucocorticoids, cyclosporine A, and JTE-607 [(-)ethyl-N-{3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl) ethoxy] benzoyl}-L-phenylalaninate dihydrochloride], a proinflammatory cytokine inhibitor that does not inhibit interleukin (IL)-2 or interferon-gamma, were compared in a mouse septic shock model induced by cecal ligation and puncture (CLP). CLP caused elevation of macrophage inflammatory protein (MIP)-2 in lung, and MIP-2 and IL-6 in plasma and peritoneal fluid, reaching a peak 4 to 8 h after CLP. Myeloperoxidase (MPO) activity in lung increased and reached a peak 8 to 12 h after CLP. Acute treatment (subcutaneous injections 1 h before and 2 h after CLP) of mice with JTE-607 and methylprednisolone showed significant inhibition of elevated cytokine levels and MPO activity, plus increased survival rate. Similar treatment with cyclosporine A and prednisolone was ineffective. Chronic treatment (subcutaneous injection for seven consecutive days before CLP) of mice with JTE-607 also showed an inhibitory effect on cytokine production, MPO activity and mortality. In contrast, chronic treatment with cyclosporine A and prednisolone did not inhibit cytokine production or MPO activity, but rather exacerbated mortality. These results indicate that JTE-607 has protective effect on mouse mortality induced by CLP, correlating with inhibition of proinflammatory cytokines, whereas the immunosuppressants cyclosporine A and prednisolone do not. This suggests that JTE-607, a multiple cytokine inhibitor that does not cause adverse immunosuppression, is useful for treatment of septic shock.