针刺对乳腺癌化疗后癌因性疲乏模型小鼠肠-脑轴相关因子的影响

Effect of acupuncture on gut-brain axis-associated molecular profiles in mouse models of cancer-related fatigue after chemotherapy for breast cancer

摘要:

目的 观察针刺对乳腺癌化疗后癌因性疲乏（CRF）模型小鼠肠-脑轴相关因子的影响，探讨针刺改善乳腺癌CRF的可能机制。方法 将BALB/c小鼠随机分为空白组、模型组、针刺组和假针刺组，以荷瘤加化疗的方法复制乳腺癌化疗后CRF模型小鼠。针刺足三里、三阴交、百会、关元、气海穴位，1次/d，30 min/次，干预14 d。通过小鼠一般情况、强迫游泳实验、旷场实验评估小鼠体力和疲劳情况；Western blotting检测下丘脑和结肠组织中炎症因子白细胞介素-1β（IL-1β）、IL-6、肿瘤坏死因子-α（TNF-α）蛋白表达；酶联免疫吸附试验检测血清HPA轴相关因子皮质醇（CORT）、促肾上腺皮质激素（ACTH）表达。结果 模型组模型复制后强迫游泳不动时间长于空白组（P <0.05）。模型组干预后强迫游泳不动时间长于针刺组（P <0.05），假手术组干预后长于针刺组（P <0.05）。模型组模型复制后水平运动得分、垂直运动得分低于对照组（P <0.05）。针刺组干预后水平运动得分、垂直运动得分高于模型组、假针刺组（P <0.05）。模型组、假针刺组小鼠下丘脑中IL-1β、IL-6、TNF-α蛋白相对表达量高于空白组（P <0.05），针刺组低于模型组、假针刺组（P <0.05）。针刺组、模型组、假针刺组结肠组织中IL-1β、IL-6、TNF-α蛋白相对表达量高于空白组（P <0.05），针刺组低于模型组、针刺组（P <0.05）。模型组、假针刺组ACTH蛋白水平高于空白组（P <0.05），CORT蛋白水平低于空白组（P <0.05）；针刺组ACTH蛋白水平低于模型组（P <0.05），CORT蛋白水平高于模型组（P <0.05）；针刺组ACTH蛋白水平低于假针刺组（P <0.05），CORT蛋白水平高于假针刺组（P <0.05）。结论 针刺可能通过降低乳腺癌CRF模型小鼠中枢和结肠中促炎因子的表达水平，调节HPA轴功能紊乱状态，进而改善乳腺癌化疗后CRF的疲乏症状，这可能是针刺治疗CRF的作用机制之一。

Abstract:

Objective To observe the effect of acupuncture on gut-brain axis-associated molecular profiles in mouse models of cancer-related fatigue (CRF) after chemotherapy for breast cancer, and to explore the possible mechanism underlying the improvement of CRF in breast cancer mediated by acupuncture.Methods BALB/c mice were randomly divided into blank group, model group, acupuncture group and sham acupuncture group. The tumor-bearing mice subjected to chemotherapy were used to establish models of CRF after chemotherapy for breast cancer. Acupoints including "Zusanli", "Sanyinjiao", "Baihui", "Guanyuan", and "Qihai" were selected for acupuncture, and the mice underwent 30-minute treatment once a day for 14 days. The physical strength and fatigue of mice were evaluated through general conditions, forced swimming tests, and open field tests. Western blotting was performed to detect the protein expressions of inflammatory factors IL-1β, IL-6, and TNF-α in hypothalamus and colon tissues. ELISA was used to determine the serum levels of CORT and ACTH associated with the hypothalamic-pituitary-adrenal (HPA) axis.Results The immobility time during the forced swimming tests in the model group was longer than that in the blank group (P < 0.05). Compared with the acupuncture group, the immobility time during the forced swimming tests before and after the intervention was longer in the model group (P < 0.05). Besides, the immobility time during the forced swimming tests in the sham operation group was longer than that in the acupuncture group (P < 0.05). The scores of horizontal and vertical movements in the model group were lower than those in the blank group (P < 0.05). The scores of horizontal and vertical movements in the acupuncture group were higher than those in the model group and the sham acupuncture group (P < 0.05). The relative protein expressions of IL-1β, IL-6, and TNF-α in the hypothalamus of mice in the model group and the sham acupuncture group were higher than those in the blank group (P < 0.05), while those in the acupuncture group were lower relative to those in the model group and the sham acupuncture group (P < 0.05). The relative protein expressions of IL-1β, IL-6, and TNF-α in the colon tissues of mice in the acupuncture group, model group and the sham acupuncture group were all higher than those in the blank group (P < 0.05), those in the acupuncture group were lower than those in the model group (P < 0.05), and those in the acupuncture group were lower than those in the sham acupuncture group (P < 0.05). The protein level of ACTH in the model group and the sham acupuncture group was higher than that in the blank group (P < 0.05), whereas the protein level of CORT in the model group and the sham acupuncture group was lower than that in the blank group (P < 0.05). The protein level of ACTH in the acupuncture group was lower than that in the model group (P < 0.05), whereas the protein level of CORT in the acupuncture group was higher than that in the model group (P < 0.05). The protein level of ACTH in the acupuncture group was lower than that in the sham acupuncture group (P < 0.05), whereas the protein level of CORT in the acupuncture group was higher than that in the sham acupuncture group (P < 0.05).Conclusion Acupuncture could mitigate the fatigue in mouse models of CRF after chemotherapy for breast cancer, possibly by reducing the expressions of proinflammatory factors in the central nervous system and the colon and modulating the dysfunction of the HPA axis, which may also be part of the mechanisms underlying the roles of acupuncture in treating CRF.