Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages.
Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages.
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DOI：
10.3390/antiox11102050
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发表时间：
2022-10-18
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影响因子：
--
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中科院分区：
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--
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头颈癌的放射治疗经常导致唾液腺长期功能低下，严重影响生活质量并且难以治疗。在这里，我们研究了 1-磷酸鞘氨醇 (S1P)（一种多功能信号鞘脂）在预防放疗引起的不可逆口干方面的作用和机制。小鼠颌下腺 (SMG) 接受或不接受 SMG 内 S1P 预处理的照射。在毛果芸香碱刺激后测量唾液流速。通过流式细胞术、免疫组织化学、定量 RT-PCR、蛋白质印迹和/或单细胞 RNA 测序检查与 S1P 信号传导和辐射损伤相关的基因表达。 S1P预处理通过减少辐射诱导的氧化应激以及随后的细胞凋亡和细胞衰老来改善辐射诱导的小鼠唾液功能障碍，这与Nrf2调节的抗氧化反应的增强有关。在小鼠 SMG 中，内皮细胞和常驻巨噬细胞是能够产生 S1P 并表达促再生 S1P 受体 S1pr1 的主要细胞。 S1P 预处理可能通过 S1pr1/Akt/eNOS 轴保护小鼠 SMG 和人内皮细胞免受辐射损伤。此外，在小鼠模型中，SMG 内注射 S1P 不会影响头颈癌的生长和放射敏感性。这些数据表明 S1P 信号通路是缓解辐射引起的唾液腺功能减退的有希望的靶标。
Radiotherapy for head-and-neck cancers frequently causes long-term hypofunction of salivary glands that severely compromises quality of life and is difficult to treat. Here, we studied effects and mechanisms of Sphingosine-1-phosphate (S1P), a versatile signaling sphingolipid, in preventing irreversible dry mouth caused by radiotherapy. Mouse submandibular glands (SMGs) were irradiated with or without intra-SMG S1P pretreatment. The saliva flow rate was measured following pilocarpine stimulation. The expression of genes related to S1P signaling and radiation damage was examined by flow cytometry, immunohistochemistry, quantitative RT-PCR, Western blotting, and/or single-cell RNA-sequencing. S1P pretreatment ameliorated irradiation-induced salivary dysfunction in mice through a decrease in irradiation-induced oxidative stress and consequent apoptosis and cellular senescence, which is related to the enhancement of Nrf2-regulated anti-oxidative response. In mouse SMGs, endothelial cells and resident macrophages are the major cells capable of producing S1P and expressing the pro-regenerative S1P receptor S1pr1. Both mouse SMGs and human endothelial cells are protected from irradiation damage by S1P pretreatment, likely through the S1pr1/Akt/eNOS axis. Moreover, intra-SMG-injected S1P did not affect the growth and radiosensitivity of head-and-neck cancer in a mouse model. These data indicate that S1P signaling pathway is a promising target for alleviating irradiation-induced salivary gland hypofunction.
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影响因子：
12.4
作者：
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作者：
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Hla T
影响因子：
12.4
作者：
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DOI：
10.1016/j.ijrobp.2008.09.036
发表时间：
2009-02-01
影响因子：
7
作者：
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通讯作者：
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影响因子：
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Bruni P