| 徐化雪,王 佳,李俊峰.基于TLR4/MyD88/NF-κB信号通路研究右美托咪定对肝癌切除术大鼠免疫功能的影响[J].肿瘤学杂志,2021,27(6):466-473. |
| 基于TLR4/MyD88/NF-κB信号通路研究右美托咪定对肝癌切除术大鼠免疫功能的影响 |
| Study on the Effect of Dexmedetomidine on the Immune Function of Rats Undergoing Liver Cancer Resection Based on TLR4/MyD88/NF-κB Signaling Pathway |
| 投稿时间：2021-01-23 |
| DOI：10.11735/j.issn.1671-170X.2021.06.B010 |
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| 中文关键词: 右美托咪定 肝癌切除术 免疫功能 TLR4/MyD88/NF-κB |
| 英文关键词:dexmedetomidine hepatoma surgery immune function TLR4/MyD88/NF-κB |
| 基金项目:浙江省医药卫生科技计划项目（2018KY001，2021KY012）；浙江省医学会临床科研基金项目（2018ZYC?鄄A02） |
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| 中文摘要: |
| 摘 要：［目的］ 基于TLR4/MyD88/NF-κB信号通路探讨右美托咪定对肝癌切除术大鼠免疫功能的影响。［方法］ 采用肝包膜下植入肝癌组织建立大鼠原位肝癌模型，并以随机数字表法将24只原位肝癌SD大鼠分为对照组（C组）和右美托咪定低、中、高剂量组（DL组、DM组、DH组），每组6只大鼠。右美托咪定组大鼠于麻醉诱导前15min内静脉输注右美托咪定，麻醉诱导插管后，持续静脉输注右美托咪定至实验结束，对照组则静脉输注等量生理盐水。各组分别于术前（T0）、术后2d（T1）和术后5d（T2）采集尾静脉血。采用流式细胞仪测定T淋巴细胞亚群CD3+、CD4+、CD8+水平，计算CD4+/CD8+；采用ELISA法检测血浆白细胞介素-2（IL-2）、白细胞介素-10（IL-10）、白细胞介素-17A（IL-17A）及干扰素-γ（IFN-γ）的浓度；T2取血后，处死大鼠，观察脾组织病理变化，并运用Western blot检测脾组织中TLR4、MyD88、NF-κB p65蛋白表达。［结果］在T1和T2时，DH组CD3+、CD4+T细胞数量均比C组显著提高(T1：45.80±8.95 vs 26.03±8.45，P＜0.05；19.73±3.23 vs 10.00±2.95，P＜0.01；T2：45.70±5.41 vs 23.77±5.98，15.30±3.15 vs 8.73±2.80，P均＜0.05)，CD8+ T细胞数量则降低，但无显著差异(P>0.05)。IL-2、IL-17A和IFN-γ水平显著提高(T1：53.72±1.32 vs 51.89±1.19，P<0.05；225.16±2.46 vs 216.80±2.77，P＜0.01；1 556.02±20.72 vs 1 528.55±19.77，P<0.05；T2：53.30±1.35 vs 49.93±1.28，P＜0.01；223.57±2.55 vs 211.42±2.61，P<0.01；1 553.81±21.24 vs 1 524.72±15.65，P<0.05)，IL-10水平降低(T1：145.56±1.50 vs 155.36±1.19；T2：148.51±1.39 vs 166.26±2.12，P均＜0.01)。与T0时比较，各组在T1、T2时CD3+、CD4+T细胞数量均降低，CD4+/ CD8+升高，CD8+T细胞数量升高。T2时，C组和DL组的IL-2、IL-17A水平均显著降低（C组：49.93±1.28 vs 56.02±0.98，211.42±2.61 vs 226.77±2.59，P均＜0.01；DL组：50.77±0.83 vs 55.02±1.13，P＜0.01；219.67±2.03 vs 225.82±2.64，P<0.05），IL-10水平显著升高（166.26±2.12 vs 146.28±1.50，155.40±1.57 vs 143.59±1.19，P均＜0.01），各组在T1、T2时IFN-γ水平无显著变化。病理结果显示，与C组相比，右美托咪定组脾脏中成熟淋巴细胞数量增加，白髓面积相对扩大。Western blot结果显示，右美托咪定呈剂量依赖性显著下调TLR4、MyD88和NF-κB p65的表达。［结论］ 右美托咪定可改善原位肝癌切除术大鼠术后细胞免疫功能抑制，可能是通过阻碍TLR4/MyD88/NF-κB信号通路的激活而发挥免疫调节作用。 |
| 英文摘要: |
| Abstract：［Objective］ To explore the effect of dexmedetomidine on the immune function of rats undergoing liver cancer resection based on TLR4/MyD88/NF-κB signaling pathway. ［Methods］ Orthotopic liver cancer was induced by intrahepatic tumor implantation with Walker-256 cells. Twenty-four male SD rats were randomly divided into dexmedetomidine low，medium，high dose group(group DL，DM，DH) and control group(group C) with 6 rats in each group. Rats in the dexmedetomidine group were intravenously infused with dexmedetomidine within 15 minutes before induction of anesthesia. After intubation of anesthesia induction，the rats were continuously infused with dexmedetomidine until the end of the experiment. The equal volume of normal saline was administered in group C. In each group，blood was obtained from the tail vein before operation(T0)，2 days after operation(T1) and 5 days after operation(T2). The levels of T lymphocyte subsets(CD3+，CD4+，CD8+) were determined by flow cytometry. CD4+/CD8+ ratio was calculated. Plasma interleukin-2(IL-2)，interleukin-10(IL-10)，interleukin-17A(IL-17A) and interferon-γ(IFN-γ) were detected by ELISA methods. After taking blood from T2，the rats were sacrificed to observe the pathological changes of spleen tissues，and Western blot was used to detect the protein expression of TLR4，MyD88 and NF-κB p65 in spleen.［Results］ At T1 and T2，the number of CD3+ and CD4+ T cells significantly increased in group DH than those in group C(T1：45.80±8.95 vs 26.03±8.45，P＜0.05；19.73±3.23 vs 10.00±2.95，P＜0.01；T2：45.70±5.41 vs 23.77±5.98，15.30±3.15 vs 8.73±2.80，all P＜0.05)，and the number of CD8+T cells reduced but not significantly. The levels of IL-2，IL-17A and IFN-γ significantly increased(T1：53.72±1.32 vs 51.89±1.19，P<0.05；225.16±2.46 vs 216.80±2.77，P＜0.01；1 556.02±20.72 vs 1 528.55±19.77，P<0.05；T2：53.30±1.35 vs 49.93±1.28，P＜0.01；223.57±2.55 vs 211.42±2.61，P<0.01；1 553.81±21.24 vs 1 524.72±15.65，P<0.05)，while IL-10 reduced(T1：145.56±1.50 vs 155.36±1.19，T2：148.51±1.39 vs 166.26±2.12，all P＜0.01). Compared with T0，the CD4+/CD8+ ratios，level of CD3+ and CD4+ T cells reduced and CD8+ T cells increased at T1 and T2 in each group. The levels of IL-2 and IL-17A significantly reduced(group C：49.93±1.28 vs 56.02±0.98，211.42±2.61 vs 226.77±2.59，all P＜0.01；group DL：50.77±0.83 vs 55.02±1.13，P＜0.01；219.67±2.03 vs 225.82±2.64，P<0.05) and IL-10 significantly increased at T2 in group C and DL(166.26±2.12 vs 146.28±1.50，155.40±1.57 vs 143.59±1.19，all P＜0.01). There was no significant change in IFN-γ levels at T1 and T2 in each group. Pathological results showed that，the number of mature lymphocytes in the spleen of the dexmedetomidine group increased，the area of white pulp was relatively enlarged compared with group C. Western blot results showed that，dexmedetomidine down-regulated the expression of TLR4，MyD88 and NF-κB p65 in a dose-dependent manner. ［Conclusion］ Dexmedetomidine could improve the suppression of cellular immune function in rats after orthotopic liver cancer resection，which may play an immunomodulatory effect by blocking the activation of TLR4/MyD88/NF-κB signaling pathway. |
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