Huang Tien-Yu, Yang Sung-Sen, Liao Ching-Len, Lin Ming-Hong, Lin Hsuan-Hwai, Lin Jung-Chun, Chen Peng-Jen, Shih Yu-Lueng, Chang Wei-Kuo, Hsieh Tsai-Yuan
Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Taiwan Association for the Study of Small Intestinal Diseases, Taoyuan, Taiwan.
Front Oncol. 2021 Nov 23;11:733555. doi: 10.3389/fonc.2021.733555. eCollection 2021.
Ste20-related protein proline/alanine-rich kinase (SPAK) affects cell proliferation, differentiation, and transformation, and sodium and chloride transport in the gut. However, its role in gut injury pathogenesis is unclear.
We determined the role of SPAK in chemotherapy-induced intestinal mucositis using and models.
Using SPAK-knockout (KO) mice, we evaluated the severity of intestinal mucositis induced by 5-fluorouracil (5-FU) by assessing body weight loss, histological changes in the intestinal mucosa, length of villi in the small intestine, pro-inflammatory cytokine levels, proliferative indices, and apoptotic indices. We also evaluated changes in gut permeability and tight junction-associated protein expression. Changes in cell permeability, proliferation, and apoptosis were assessed in SPAK siRNA-transfected 5FU-treated IEC-6 cells.
5-FU-treated SPAK-KO mice exhibited milder intestinal mucositis, reduced pro-inflammatory cytokine expression, increased villus length, good maintenance of proliferative indices of villus cells, decreased apoptotic index of enterocytes, reduced gut permeability, and restoration of tight junction protein expression (. 5-FU-treated wild-type mice). Under conditions, siRNA-mediated SPAK-knockdown in IEC-6 cells decreased cell permeability and maintained homeostasis following 5-FU treatment.
SPAK deficiency attenuated chemotherapy-induced intestinal mucositis by modulating gut permeability and tight junction-associated protein expression and maintaining gut homeostasis in murine small intestinal tissues following gut injury. The expression of SPAK may influence the pathogenesis of chemotherapy-induced intestinal mucositis.
丝氨酸/苏氨酸蛋白激酶20相关富含脯氨酸/丙氨酸激酶（SPAK）影响细胞增殖、分化和转化，以及肠道中的钠和氯转运。然而，其在肠道损伤发病机制中的作用尚不清楚。
我们使用[具体模型1]和[具体模型2]模型确定了SPAK在化疗诱导的肠道黏膜炎中的作用。
使用SPAK基因敲除（KO）小鼠，我们通过评估体重减轻、肠黏膜组织学变化、小肠绒毛长度、促炎细胞因子水平、增殖指数和凋亡指数，来评估5-氟尿嘧啶（5-FU）诱导的肠道黏膜炎的严重程度。我们还评估了肠道通透性和紧密连接相关蛋白表达的变化。在转染了SPAK siRNA的5FU处理的IEC-6细胞中评估细胞通透性、增殖和凋亡的变化。
5-FU处理的SPAK-KO小鼠表现出较轻的肠道黏膜炎、促炎细胞因子表达降低、绒毛长度增加、绒毛细胞增殖指数良好维持、肠上皮细胞凋亡指数降低、肠道通透性降低以及紧密连接蛋白表达恢复（与5-FU处理的野生型小鼠相比）。在[具体条件]下，IEC-6细胞中siRNA介导的SPAK敲低降低了细胞通透性，并在5-FU处理后维持了内环境稳定。
SPAK缺乏通过调节肠道通透性和紧密连接相关蛋白表达，并在肠道损伤后维持小鼠小肠组织中的肠道内环境稳定，减轻了化疗诱导的肠道黏膜炎。SPAK的表达可能影响化疗诱导的肠道黏膜炎的发病机制。
