Institute of Biomedical Sciences, Department of Structural Biology, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil.
Faculty of Pharmaceutical Sciences, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil.
Int Immunopharmacol. 2019 May;70:324-337. doi: 10.1016/j.intimp.2019.02.032. Epub 2019 Mar 7.
We investigated the effect in vitro and in vivo of doxycycline hyclate (Dx), a broad-spectrum antibiotic inhibitor of matrix metaloproteinases (MMPs), on adult Schistosoma mansoni worms and granulomatous liver inflammation in infected mice. Adult S. mansoni worms in culture treated with different concentrations of Dx (50-180 μg/mL) were studied for eight days to assess its morphology, eggs production, and mortality. Uninfected mice and those infected with S. mansoni, untreated and treated with praziquantel (Pz; 200 mg/kg) or Dx (50 mg/kg), were evaluated for 60 days. Our results indicated that Dx induced dose-dependent integumentary lesions (bubbles, tubercle collapse, spicule disappearance, peeling, and erosion), reduced mating rate and eggs-laying in adult S. mansoni worms. The effective lethal dose required to kill 50% of worms was 112.0 μg/mL Dx (DL). In mice, S. mansoni infection induced hepatomegaly, intense IL-4, IL-10, TNF-α and TGF-β production, granulomatous inflammation and hepatic glycogen depletion. The number and size of the granulomas was similar in untreated and Dx-treated animals. Untreated animals showed a predominance of productive granulomas, and intense MMP-2 and MMP-9 activities. Dx-treated mice exhibited a significant increase in IL-4 levels, tissue inflammation, proportion of involutive granulomas, and hepatic collagenogenesis, as well as attenuated MMP-2 and MMP-9 activities. Our findings indicated that Dx is toxic to adult S. mansoni worms in vitro. However, in vitro beneficial effects were not reproduced in vivo, since Dx treatment increased liver granulomatous inflammation and collagenogenesis in S. mansoni-infected mice by a process potentially associated with Dx-mediated hepatic MMP-2 and MMP-9 inhibition.
我们研究了盐酸多西环素（Dx）对成年曼氏血吸虫（Schistosoma mansoni）蠕虫的体外和体内作用，以及对感染小鼠肝脏肉芽肿炎症的作用。Dx（50-180μg/ml）处理不同浓度的体外培养成年曼氏血吸虫蠕虫 8 天，评估其形态、产卵和死亡率。未感染的小鼠和感染曼氏血吸虫的小鼠，未经处理和用吡喹酮（Pz；200mg/kg）或 Dx（50mg/kg）处理，分别进行 60 天评估。我们的结果表明，Dx 诱导了与剂量相关的表皮损伤（气泡、结节塌陷、刺消失、脱皮和侵蚀），降低了成年曼氏血吸虫的交配率和产卵率。杀死 50%蠕虫所需的有效致死剂量为 112.0μg/ml Dx（DL）。在小鼠中，曼氏血吸虫感染引起肝肿大、强烈的 IL-4、IL-10、TNF-α 和 TGF-β产生、肉芽肿炎症和肝糖原耗竭。未经处理和 Dx 处理动物的肉芽肿数量和大小相似。未经处理的动物表现出增殖性肉芽肿占主导地位，以及强烈的 MMP-2 和 MMP-9 活性。Dx 处理的小鼠表现出 IL-4 水平显著升高、组织炎症、退行性肉芽肿比例增加、肝胶原生成增加，以及 MMP-2 和 MMP-9 活性减弱。我们的研究结果表明，Dx 在体外对成年曼氏血吸虫蠕虫具有毒性。然而，在体内并没有重现出体外的有益作用，因为 Dx 处理通过与 Dx 介导的肝 MMP-2 和 MMP-9 抑制相关的过程，增加了感染曼氏血吸虫的小鼠的肝脏肉芽肿炎症和胶原生成。
