Transient Activation of Hedgehog Signaling Inhibits Cellular Senescence and Inflammation in Radiated Swine Salivary Glands through Preserving Resident Macrophages.
Transient Activation of Hedgehog Signaling Inhibits Cellular Senescence and Inflammation in Radiated Swine Salivary Glands through Preserving Resident Macrophages.
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Hedgehog信号的瞬时激活通过保留驻留的巨噬细胞抑制辐射猪唾液腺中的细胞衰老和炎症。
DOI：
10.3390/ijms222413493
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发表时间：
2021-12-16
影响因子：
5.6
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Hu L;Du C;Yang Z;Yang Y;Zhu Z;Shan Z;Zhang C;Wang S;Liu F
头颈部癌放射治疗通常会对唾液腺功能造成不可逆的损害。这种损害大大降低了患者的生活质量，并且难以补救。以前，我们发现，刺猬信号的瞬时激活减轻了小鼠和猪模型辐射后的唾液功能减退，通过抑制辐射诱导的细胞衰老，这是由小鼠下颌下腺中的常驻巨噬细胞介导的。在这里，我们报告说，在猪腮腺共享许多功能与人类，刺猬受体PTCH 1主要表达在巨噬细胞，PTCH 1和多个巨噬细胞标志物的水平显着降低辐射，但恢复短暂的刺猬激活。这些腮腺巨噬细胞主要表达M2巨噬细胞标志物ARG1，而辐射促进促炎细胞因子的表达，其被短暂的Hedgehog激活逆转。Hedgehog激活可能通过抑制P53信号传导和随后的细胞衰老在辐射后保留腮腺巨噬细胞。一致地，VEGF，Hedgehog信号传导下游的必需抗衰老细胞因子，通过辐射显著降低，但通过短暂的Hedgehog激活恢复。这些发现表明，在临床相关的猪模型中，短暂的Hedgehog激活通过恢复驻留的巨噬细胞以及随后的细胞衰老和炎症抑制来恢复辐照唾液腺的功能。
Salivary gland function is commonly and irreversibly damaged by radiation therapy for head and neck cancer. This damage greatly decreases the patient’s quality of life and is difficult to remedy. Previously, we found that the transient activation of Hedgehog signaling alleviated salivary hypofunction after radiation in both mouse and pig models through the inhibition of radiation-induced cellular senescence that is mediated by resident macrophages in mouse submandibular glands. Here we report that in swine parotid glands sharing many features with humans, the Hedgehog receptor PTCH1 is mainly expressed in macrophages, and levels of PTCH1 and multiple macrophage markers are significantly decreased by radiation but recovered by transient Hedgehog activation. These parotid macrophages mainly express the M2 macrophage marker ARG1, while radiation promotes expression of pro-inflammatory cytokine that is reversed by transient Hedgehog activation. Hedgehog activation likely preserves parotid macrophages after radiation through inhibition of P53 signaling and consequent cellular senescence. Consistently, VEGF, an essential anti-senescence cytokine downstream of Hedgehog signaling, is significantly decreased by radiation but recovered by transient Hedgehog activation. These findings indicate that in the clinically-relevant swine model, transient Hedgehog activation restores the function of irradiated salivary glands through the recovery of resident macrophages and the consequent inhibition of cellular senescence and inflammation.
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在小型猪模型中，腺内 Shh 基因传递减轻了辐射引起的唾液分泌不足。
影响因子：
12.4
作者：
Hu L;Zhu Z;Hai B;Chang S;Ma L;Xu Y;Li X;Feng X;Wu X;Zhao Q;Qin L;Wang J;Zhang C;Liu F;Wang S
通讯作者：
Wang S
影响因子：
11.2
作者：
Keysar SB;Le PN;Anderson RT;Morton JJ;Bowles DW;Paylor JJ;Vogler BW;Thorburn J;Fernandez P;Glogowska MJ;Takimoto SM;Sehrt DB;Gan GN;Eagles-Soukup JR;Serracino H;Hirsch FR;Lucia MS;Thorburn A;Song JI;Wang XJ;Jimeno A
通讯作者：
Jimeno A
影响因子：
4.4
作者：
Gluck C;Min S;Oyelakin A;Smalley K;Sinha S;Romano RA
通讯作者：
Romano RA
影响因子：
4
作者：
Hai, Bo;Yang, Zhenhua;Liu, Fei
通讯作者：
Liu, Fei
影响因子：
2.4
作者：
Amano O;Mizobe K;Bando Y;Sakiyama K
通讯作者：
Sakiyama K