GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat
GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat
复制标题
DOI：
10.1016/j.freeradbiomed.2009.04.014
复制
发表时间：
2009-07-01
影响因子：
7.4
通讯作者：
Moore, Philip K.
中科院分区：
文献类型：
--
作者：
Li, Ling;Salto-Tellez, Manuel;Moore, Philip K.
GYY4137（吗啉-4-鎓-4-甲氧基苯基（吗啉）二硫代膦）是一种缓慢释放硫化氢 (H2S) 供体。脂多糖（LPS；4 mg/kg，静脉注射）后 10 分钟，对麻醉大鼠给予 GYY4137（50 mg/kg，静脉注射）可减少缓慢发展的低血压。 GYY4137 抑制大鼠血液中 LPS 诱导的 TNF-α 产生，并减少 LPS 引起的 NF-κ B;B 激活、诱导型一氧化氮合酶/环氧合酶-2 表达以及 RAW 264.7 巨噬细胞中 PGE(2) 和硝酸盐/亚硝酸盐的生成。 LPS 后 1 或 2 小时（但不是之前 1 小时）给予清醒大鼠 GYY4137（50 mg/kg，腹腔注射）可降低随后（4 小时）血浆促炎细胞因子（TNF-α、IL-1β、IL-6）、亚硝酸盐/硝酸盐、C 反应蛋白和 L-选择素的升高。 GYY4137 给药还减少了 LPS 引起的肺髓过氧化物酶活性的增加，增加了抗炎细胞因子 IL-10 的血浆浓度，并减少了组织损伤（根据组织学和血浆肌酐和丙氨酸转氨酶活性的测量确定）。 Tune 过期的 GYY4137（50 mg/kg，腹腔注射）不会影响 LPS 诱导的血浆 TNF-α 或肺髓过氧化物酶活性的升高。 GYY4137 还降低了 LPS 介导的肝转录因子（NF-κ B 和 STAT-3）的上调。这些结果表明 GYY4137 具有所有抗炎作用。 GYY4137 和其他缓慢释放的 H2S 供体在其他炎症模型和人类中发挥抗炎活性的可能性值得进一步研究。 (C) 2009 Elsevier Inc. 保留所有权利。
GYY4137 (morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate) is a slow-releasing hydrogen sulfide (H2S) donor. Administration of GYY4137 (50 mg/kg, iv) to anesthetized rats 10 min after lipopolysaccharide (LPS; 4 mg/kg, iv) decreased the slowly developing hypotension. GYY4137 inhibited LPS-induced TNF-alpha production in rat blood and reduced the LPS-evoked rise in NF-kappa B;B activation, inducible nitric oxide synthase/cyclooxygenase-2 expression, and generation of PGE(2) and nitrate/nitrite in RAW 264.7 macrophages. GYY4137 (50 mg/kg, ip) administered to conscious rats 1 or 2 h after (but not 1 h before) LPS decreased the subsequent (4 h) rise in plasma proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6), nitrite/nitrate, C-reactive protein, and L-selectin. GYY4137 administration also decreased the LPS-evoked increase in lung myeloperoxidase activity, increased plasma concentration of the anti-inflammatory cytokine IL-10, and decreased tissue damage as determined histologically and by measurement of plasma creatinine and alanine aminotransferase activity. Tune-expired GYY4137 (50 mg/kg, ip) did not affect the LPS-induced rise in plasma TNF-alpha or lung myeloperoxidase activity. GYY4137 also decreased the LPS-mediated upregulation of liver transcription factors (NF-kappa B and STAT-3). These results suggest ail anti-inflammatory effect of GYY4137. The possibility that GYY4137 and other slow-releasing H2S donors exert anti-inflammatory activity in other models of inflammation and in humans warrants further study. (C) 2009 Elsevier Inc. All rights reserved.