Doxycycline inhibits inflammation-induced lymphangiogenesis in mouse cornea by multiple mechanisms.
Doxycycline inhibits inflammation-induced lymphangiogenesis in mouse cornea by multiple mechanisms.
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DOI：
10.1371/journal.pone.0108931
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Liang D
中科院分区：
文献类型：
--
作者：
Han L;Su W;Huang J;Zhou J;Qiu S;Liang D
淋巴管生成显着参与疾病的发病机制，包括移植物排斥、癌症转移和各种炎症状况。抑制淋巴管生成已成为治疗这些疾病的新治疗靶点。在这里，我们探讨了强力霉素在角膜炎症诱导的淋巴管生成（ILA）中的抗淋巴管生成作用及其潜在机制。在本研究中，患有角膜 ILA 的小鼠接受局部强力霉素 (0.1%) 或载体对照治疗。使用淋巴管内皮透明质酸受体-1 (LYVE-1) 的角膜免疫染色来量化淋巴管生成。使用人真皮淋巴内皮细胞（HDLEC）和鼠巨噬细胞系（RAW264.7）进一步探索体外多西环素介导的抗淋巴管生成的潜在机制。我们的结果表明，多西环素治疗显着抑制小鼠角膜中的 ILA (p<0.001)，血管内皮生长因子 (VEGF)-C/VEGF 受体 3 信号传导、巨噬细胞浸润和炎症细胞因子表达显着降低。多西环素还通过调节 PI3K/Akt/内皮一氧化氮 (NO) 合酶 (eNOS) 通路显着抑制 VEGF-C 诱导的 HDLEC 增殖，并通过调节 PI3K/Akt/核因子-kappaB (NF-κB) 通路显着抑制 RAW264.7 细胞系中白介素-1β (IL-1β)、TNF-α 和 VEGF-C 的产生。此外，强力霉素治疗可显着降低 ILA 中 NF-κBp65、Akt 和 eNOS 的磷酸化，并显着抑制体外和 ILA 中的基质金属蛋白酶 (MMP) 活性。总之，多西环素可能通过抑制 VEGF-C 信号传导、巨噬细胞功能和 MMP 活性来抑制 ILA。这一观察结果表明多西环素是淋巴管生成相关疾病的潜在治疗剂。
Lymphangiogenesis is significantly involved in the pathogenesis of diseases, including graft rejection, cancer metastasis and various inflammatory conditions. The inhibition of lymphangiogenesis has become a new therapeutic target for the treatment of these diseases. Here, we explored the anti-lymphangiogenic effects of doxycycline in inflammation-induced lymphangiogenesis (ILA) in the cornea and the underlying mechanisms. In the present study, mice with ILA of the cornea were treated with topical doxycycline (0.1%) or vehicle control. Lymphangiogenesis was quantified using corneal immunostaining of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). Human dermal lymphatic endothelial cells (HDLECs) and a murine macrophage cell line (RAW264.7) were used to further explore the underlying mechanisms of doxycycline-mediated anti-lymphangiogenesis in vitro. Our results showed that doxycycline treatment dramatically inhibited ILA in the mouse cornea (p<0.001), with a significant decrease in vascular endothelial growth factor (VEGF)-C/VEGF receptor 3 signalling, macrophage infiltration and inflammatory cytokine expression. Doxycycline also significantly inhibited VEGF-C-induced HDLEC proliferation in vitro by modulating the PI3K/Akt/endothelial nitric oxide (NO) synthase (eNOS) pathway and significantly suppressed interleukin-1β (IL-1β), TNF-α and VEGF-C production in the RAW264.7 cell line by modulating the PI3K/Akt/nuclear factor-kappaB (NF-κB) pathway. Additionally, doxycycline treatment dramatically reduced the phosphorylation of NF-κBp65, Akt and eNOS in ILA and significantly inhibited matrix metalloproteinases (MMPs) activity in vitro and in ILA. In conclusion, doxycycline inhibited ILA, possibly through suppression of VEGF-C signalling, macrophage function and MMPs activity. This observation suggests that doxycycline is a potential therapeutic agent for lymphangiogenesis-related diseases.
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影响因子：
3.7
作者：
Aziz M;Jacob A;Matsuda A;Wu R;Zhou M;Dong W;Yang WL;Wang P
通讯作者：
Wang P
影响因子：
2.8
作者：
Cursiefen, C;Chen, L;Streilein, JW
通讯作者：
Streilein, JW
影响因子：
6.7
作者：
Debrah, Alexander Yaw;Mand, Sabine;Hoerauf, Achim
通讯作者：
Hoerauf, Achim
DOI：
10.1196/annals.1413.020
发表时间：
2008-01-01
期刊：
LYMPHATIC CONTINUUM REVISITED
影响因子：
--
作者：
Achen, Marc G.;Stacker, Steven A.
通讯作者：
Stacker, Steven A.
影响因子：
82.9
作者：
Chen, L;Hamrah, P;Dana, MR
通讯作者：
Dana, MR