Intraperitoneal injection of tetracyclines protects mice from lethal endotoxemia downregulating inducible nitric oxide synthase in various organs and cytokine and nitrate secretion in blood
Intraperitoneal injection of tetracyclines protects mice from lethal endotoxemia downregulating inducible nitric oxide synthase in various organs and cytokine and nitrate secretion in blood
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DOI：
10.1128/aac.41.1.117
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发表时间：
1997-01-01
影响因子：
4.9
通讯作者：
Cillari, E
中科院分区：
文献类型：
--
作者：
Milano, S;Arcoleo, F;Cillari, E
我们已经测试了四环素类药物（四环素）是否能够保护小鼠免受脂多糖（LPS）诱导的休克，这是一种四环素介导的炎症反应。小鼠，注射单剂量四环素碱（TETb; 1.5、10和20 mg/kg体重）或多西环素（DOXY; 1.5 mg/kg），显著保护免于致死性腹腔内注射LPS（每只小鼠500 μ g），TdR在响应LPS而触发的早期事件中起作用;事实上，如果在注射内毒素后超过1小时注射，它们不再具有显著的保护作用。LPS处理的小鼠受Tclad保护，显示出显著抑制血液中肿瘤坏死因子α（TNF-α）、白细胞介素-1 α（IL-1 α）和硝酸盐分泌，这些事件与存活率直接相关。与单独用LPS处理的小鼠相比，在用THBE处理的小鼠中，在脾和腹膜细胞中观察到诱导型一氧化氮合酶（iNOS）活性的显著降低。此外，还发现雷公藤多甙可抑制LPS刺激的腹腔巨噬细胞合成NO。这些结果表明，Tcl 4不能直接影响这些细胞因子的合成，但它们可能调节其他途径，这些途径反过来可能负责抑制IL-1 α和TNF-α的合成。总而言之，这些结果表明TET是预防和治疗小鼠感染性休克的有利候选药物，具有抗微生物活性和抑制内源性TNF-alpha、IL-1 alpha和iNOS的能力，从而发挥有效的抗炎作用。
We have tested whether tetracyclines (TETs) are able to protect mice from lipopolysaccharide (LPS)-induced shock, a cytokine-mediated inflammatory reaction. Mice, injected with a single dose of tetracycline base (TETb; 1.5, 10, and 20 mg/kg of body weight) or doxycycline (DOXY; 1.5 mg/kg), were significantly protected from a lethal intraperitoneal injection of LPS (500 mu g per mouse), TETs acted in early events triggered in response to LPS; in fact, they were no longer significantly protective if injected more than 1 h after the injection of endotoxin. LPS-treated mice protected by TETs showed a significant inhibition of tumor necrosis factor alpha (TNF-alpha), interleukin-l alpha (IL-1 alpha), and nitrate secretion in the blood, events that were directly related with the survival. In mice treated with TETs a significant decrease of inducible nitric oxide synthase (iNOS) activity was observed in spleen and peritoneal cells compared with that detected in mice treated with LPS alone. Furthermore, TETs were found to inhibit NO synthesis by peritoneal macrophages stimulated in vitro with LPS. On the contrary, TETs were unable to decrease the ability of the macrophages to synthesize IL-1 alpha and TNF-alpha in vitro, These results indicate that TETs are not able to Bet directly on the synthesis of these cytokines, but they may modulate other pathways that could in turn be responsible for the inhibition of IL-1 alpha, and TNF-alpha synthesis. Altogether, these results indicate that TETs are advantageous candidates for the prophylaxis and treatment of septic shock in mice, having both antimicrobial activity and the ability to inhibit endogenous TNF-alpha, IL-1 alpha, and iNOS, hence, exerting, potent anti-inflammatory effects.