Nerve growth factor protects salivary glands from irradiation-induced damage
Nerve growth factor protects salivary glands from irradiation-induced damage
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神经生长因子保护唾液腺免受辐射引起的损伤
DOI：
10.1016/j.lfs.2020.118748
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发表时间：
2021-01-15
期刊：
影响因子：
6.1
通讯作者：
Li, Long-Jiang
中科院分区：
文献类型：
--
作者：
Li, Shen-Sui;Wu, Chen-Zhou;Li, Long-Jiang
目的：放射治疗已成为头颈部肿瘤的基本治疗手段。然而，放射治疗导致不可避免的副作用，特别是放射性涎腺炎，这显着损害生活质量。以前的研究表明，神经生长因子（NGF）具有辐射防护作用，但其机制尚未确定在唾液腺。本研究旨在探讨神经生长因子（NGF）对放射性唾液腺损伤的保护作用及其机制。主要方法：选用人唾液腺细胞（HSG）和C57 BL/6小鼠，建立放射性唾液腺损伤的体内外模型。利用重组NGF蛋白、NGF siRNA和过表达质粒对NGF进行体外表达调控。通过颌下腺导管将腺相关病毒-神经生长因子（AAV-NGF）逆行灌注到颌下腺（SMG）中，以操纵NGF在体外的表达。应用小分子抑制剂和siRNA抑制AKT和JNK。通过Western blotting、定量PCR、流式细胞术和组织学检测分析了NGF的功能作用和机制。主要发现：我们的研究表明，人HSG细胞和小鼠SMG组织中的NGF表达在放疗后均上调。NGF可减少IR诱导的HSG细胞凋亡，AAV介导的基因治疗可恢复唾液流率，保护唾液腺免受IR诱导的凋亡。从机理上讲，NGF通过去磷酸化JNK激酶而不是促进AKT磷酸化来保护唾液腺免受IR诱导的细胞凋亡。
Aims: Radiotherapy has become a basic treatment modality for head and neck cancer. However, radiotherapy results in inevitable side effects, particularly radiation sialadenitis, that significantly impairs quality of life. A previous study indicated that nerve growth factor (NGF) has a radio-protective effect, but the mechanism was not determined in salivary glands. In this study, we explored the functional role and mechanism regarding how NGF protects salivary glands against IR-induced damage.Main methods: Human salivary gland (HSG) cells and C57BL/6 mice were selected to establish an IR-induced salivary gland damage model in vitro and in vivo. Recombinant NGF protein and NGF siRNA and overexpression plasmids were applied to manipulate NGF expression in vitro. AAV-NGF was retrogradely perfused into the submandibular gland (SMG) through the SMG duct to manipulate NGF expression in vitro. Small-molecule inhibitors and siRNAs were applied to inhibit AKT and JNK. Western blotting, quantitative PCR, flow cytometry and histology assays were performed to analyse the functional role and mechanism of NGF.Key findings: Our study demonstrated that NGF expression was upregulated following radiotherapy both in human HSG cells and mouse SMG tissues. NGF could reduce IR-induced HSG cell apoptosis, and AAV-mediated gene therapy could restore the salivary flow rate and protect the salivary gland against IR-induced apoptosis in vivo. Mechanistically, NGF protects salivary glands from IR-induced apoptosis by de-phosphorylating JNK kinase rather than promoting AKT phosphorylation.Significance: The current study findings indicated that the modulation of the NGF pathway might prevent IR-induced salivary hypo-function.