Yang Tao, Zhao Qingguo, Hu Meijun, Pan Simin, Zhang Linying, Zhu Ruoxi, Zhou Bowen, Feng Xuanhe, Gao Zhenhua, Zhu Zhao, Zhang Yu, Hu Liang, Liu Fei, Shan Zhaochen
Outpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, China.
Department of Cell Biology and Genetics, School of Medicine, Texas A&M University Health Science Center, College Station, TX 77843, USA.
Antioxidants (Basel). 2022 Oct 18;11(10):2050. doi: 10.3390/antiox11102050.
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.
头颈部癌症的放射治疗常常会导致唾液腺长期功能减退，这严重影响生活质量且难以治疗。在此，我们研究了鞘氨醇-1-磷酸（S1P）这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及机制。对小鼠下颌下腺（SMG）进行照射，部分小鼠在照射前进行SMG内S1P预处理。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、定量逆转录-聚合酶链反应、蛋白质免疫印迹和/或单细胞RNA测序检测与S1P信号传导和辐射损伤相关的基因表达。S1P预处理通过降低辐射诱导的氧化应激以及随之而来的细胞凋亡和细胞衰老，改善了小鼠照射诱导的唾液功能障碍，这与Nrf2调节的抗氧化反应增强有关。在小鼠SMG中，内皮细胞和驻留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。小鼠SMG和人内皮细胞通过S1P预处理均免受辐射损伤，可能是通过S1pr1/Akt/eNOS轴。此外，在小鼠模型中，向SMG内注射S1P不影响头颈部癌症的生长和放射敏感性。这些数据表明，S1P信号通路是缓解照射诱导的唾液腺功能减退的一个有前景的靶点。
