围手术期应用乌司他丁治疗对肝细胞癌患者肝切除术后外周血Th22细胞百分比和血浆白细胞介素-22的影响*

doi:10.3969/j.issn.1672-5069.2019.05.027

摘要/Abstract

摘要： 目的观察围手术期应用乌司他丁对肝细胞癌（HCC）肝切除手术患者术后外周血Th22细胞百分比和血浆白细胞介素（IL）-22水平的影响。方法 2015年7月~2017年4月解放军昆明总医院普通外科行肝切除手术的HCC患者88例,术后51例接受常规治疗,37例另加乌司他丁治疗7 d。另选30例健康人作为对照。分离外周血单个核细胞（PBMC）,使用流式细胞术检测CD3⁺CD4⁺IL-22⁺的Th22细胞百分比,采用ELISA法检测血浆IL-22水平。对符合正态分布的计量资料比较采用独立样本t检验,对于非正态分布的计量资料比较采用Mann-Whitney检验。结果 HCC患者外周血Th22细胞百分比为（1.4±0.3） %,显著高于健康人【（0.8±0.1） %,P<0.0001】;HCC患者血浆IL-22水平为（116.9±32.6） pg/ml,亦显著高于健康人【（42.1±18.2） pg/ml,P<0.0001】;在术后3 d,乌司他丁治疗组和常规治疗组血清ALT分别为【219.4（40.1,510.9） IU/L和450.6（56.1,820.7） IU/L,P<0.05】,血清AST分别为【108.8（82.5,439.1） IU/L和257.3（115.3,7265） IU/L,P<0.01】;在术后7 d,乌司他丁治疗组和常规治疗组血清ALT分别为【72.4（25.6,471.5） IU/L和115.4（35.7,625.2） IU/L,P<0.05】,血清AST分别为【61.4（29.4,351.4） IU/L和90.5（45.5,293.8） IU/L,P<0.05】;术后3 d和术后7 d,乌司他丁治疗组外周血Th22细胞百分比分别为（1.2±0.4）%和（1.1±0.3）%,较常规治疗组显著降低【分别为（1.3±0.3）%,P<0.05和（1.3±0.2） %,P<0.05】;血浆IL-22水平分别为（98.1±20.1） pg/ml和（94.1±24.8） pg/ml,亦较常规治疗组显著降低【分别为（109.7±29.8） pg/ml,P<0.05和（110.7±37.1）%,P<0.05】。结论肝切除术后应用乌司他丁治疗可降低外周血Th22细胞比例和血浆IL-22水平,对肝功能具有一定的保护作用

关键词: 肝细胞癌, 肝切除术, 乌司他丁, Th22细胞, 白细胞介素-22

Abstract: Objective To investigate peripheral blood Th22 cells and plasma interleukin-22 （IL-22） level changes in patients with hepatocellular carcinoma（HCC） after hepatectomy and administration of ulinastatin. Methods A total of 88 patients with HCC were recruited in Department of General Surgery,Kunming General Hospital of PLA between July 2015 and April 2017,and all patients underwent hepatectomy. After the operation, 51 received routine supporting therapies and 37 received ulinastatin treatment for seven days. Thirty healthy individuals were also enrolled serving as normal controls （NC）. Peripheral blood mononuclear cells （PBMC） and plasma were isolated and percentage of CD3⁺CD4⁺IL-22⁺ Th22 cells were investigated by flow cytometry,and plasma IL-22 levels was measured by enzyme linked immunosorbent assay. The differences of Th22 percentages and IL-22 levels were compared between patients with HCC and NC. The independent samples t test was used for comparison of normally distributed continuous data, and Mann-Whitney test was used for comparison of continuous data with skewed distribution. Results Peripheral blood Th22 cell percentage in HCC patients was（1.4±0.3）%, significantly elevated than that in NC [（0.8±0.1）%,P<0.0001];plasma IL-22 level in HCC patients was （116.9±32.6） pg/ml,significantly higher than that in NC（42.1±18.2） pg/ml（P<0.01）;serum ALT level in ulinastatin-treated group and routine treatment group were [219.4（40.1,510.9） IU/L and 450.6 （56.1,820.7） IU/L,P<0.05] at the end of 3 days post-operation,and serum AST level in ulinastatin-treated group and routine treatment group were [108.8（82.5,439.1） IU/L and 257.3（115.3,7265） IU/L,P<0.01],respectively;serum ALT level in ulinastatin-treated group and routine treatment group were [72.4（25.6,471.5） IU/L and 115.4（35.7,625.2） IU/L,P<0.05] at the end of 7 days post-operation,and serum AST level in ulinastatin-treated group and routine treatment group were[61.4（29.4,351.4） IU/L and 90.5（45.5,293.8） IU/L,P<0.05],respectively;peripheral blood Th22 cell percentages were （1.2±0.4） % and （1.1±0.3） % at day 3 and at day 7 post-operation in ulinastatin- treated group,respectively,notably lower than those in routine treatment group [（1.3±0.3） %,P<0.05 and （1.3±0.2） %,P<0.05];plasma IL-22 levels were （98.1±20.1） pg/ml and（94.1±24.7） pg/ml in ulinastatin-treated group, respectively,significantly lower than those in routine treatment group[（109.7±29.8） pg/ml,P<0.05 and（110.7±37.1） %,P<0.05]. Conclusion Ulinastatin treatment might down-regulate peripheral blood Th22 cell counts and plasma IL-22 levels,showing liver function protection in patients with HCC after hepatectomy.

Key words: Hepatocellular carcinoma, Hepatectomy, Ulinastatin, Th22 cells, Interleukin-22

朱俊, 丁莹, 王世清, 张野, 刘野, 刘泽刚. 围手术期应用乌司他丁治疗对肝细胞癌患者肝切除术后外周血Th22细胞百分比和血浆白细胞介素-22的影响*[J]. 实用肝脏病杂志, 2019, 22(5): 720-723.

Zhu Jun, Ding Ying, Wang Shiqing, et al. Peripheral blood Th22 cells and plasma interleukin-22 level changes in patients with hepatocellular carcinoma after hepatectomy and administration of ulinastatin[J]. Journal of Practical Hepatology, 2019, 22(5): 720-723.

参考文献

[1] 王鹤,董家鸿,何蕾,等. 围手术期应用地塞米松对原发性肝癌患者肝切除术后肝功能的影响分析. 实用肝脏病杂志,2016,19(5):587-590.
[2] 周滨,朱李瑢,常仁安,等. 乌司他丁在肝切除围手术期对肝功能的保护作用. 中华普通外科杂志,2018,33(3):240-243.
[3] Jia L,Wu C.The biology and functions of Th22 cells. Adv Exp Med Biol,2014,841:209-230.
[4] Tamasauskiene L,Sitkauskiene B.Role of Th22 and IL-22 in pathogenesis of allergic airway diseases:Pro-inflammatory or anti-inflammatory effect Pediatr Neonatol,2018,59(4):339-344.
[5] Bruix J,Sherman M.American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma:an update. Hepatology,2011,53(3):1020-1022.
[6] Romanov AG,Smadja C,Traynor O,et al.Delayed hepatic resection of major liver injury. J Biomed Opt,2013,18(10):933-944.
[7] Atal SS,Atal S.Ulinastatin-a newer potential therapeutic option for multiple organ dysfunction syndrome. J Basic Clin Physiol Pharmacol,2016,27(2):91-99.
[8] Li X,Li X,Chi X,et al.Ulinastatin ameliorates acute kidney injury following liver transplantation in rats and humans. Exp Ther Med,2015,9(2):411-416.
[9] 邓清,张铁泉,乐问津,等. 乌司他丁联合异甘草酸镁和还原型谷胱甘肽对肝癌患者肝部分切除术后肝功能的保护效果初步研究. 实用肝脏病杂志,2018,21(3):439-422.
[10] Yang H,Mao Y,Lu X,et al.The effects of urinary trypsin inhibitor on liver function and inflammatory factors in patients undergoing hepatectomy:a prospective,randomized,controlled clinical study. Am J Surg,2011,202(2):151-157.
[11] Ji M,Chen T,Wang B,et al.Effects of ulinastatin combined with mechanical ventilation on oxygen metabolism,inflammation and stress response and antioxidant capacity of ARDS. Exp Ther Med,2018,15(6):4665-4670.
[12] He F,Song Y,Ying WJ,et al.Effects of ulinastatin on myocardial oxidative stress and inflammation in severely burned rats. Eur Rev Med Pharmacol Sci,2018,22(17):5719-5728.
[13] Fujita H,Nograles KE,Kikuchi T,et al.Human Langerhans cells induce distinct IL-22-producing CD4⁺T cells lacking IL-17 production. Proc Natl Acad Sci U S A,2009,106(51):21795-21800.
[14] Tian T,Yu S,Ma D.Th22 and related cytokines in inflammatory and autoimmune diseases. Expert Opin Ther Targets,2013,17(2):113-125.
[15] Dudakov JA,Hanash AM,van Den Brink MR. Interleukin-22: immunobiology and pathology. Annu Rev Immunol,2015,33: 747-785.
[16] Zhang Y,Cobleigh MA,Lian JQ,et al.A proinflammatory role for interleukin-22 in the immune response to hepatitis B virus. Gastroenterology,2011,141(5):1897-1906.
[17] Jiang BC,Liu X,Liu XH,et al.Notch signaling regulates circulating T helper 22 cells in patients with chronic hepatitis C. Viral Immunol,2017,30(7):522-532.
[18] Lai R,Xiang X,Mo R,et al.Protective effect of Th22 cells and intrahepatic IL-22 in drug induced hepatocellular injury. J Hepatol,2015,63(1):148-155.
[19] Mo R,Wang P,Lai R,et al.Persistently elevated circulating Th22 reversely correlates with prognosis in HBV-related acute-on-chronic liver failure. J Gastroenterol Hepatol,2017,32(3): 677-686.
[20] Jiang R,Tan Z,Deng L,et al.Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology,2011,54(3):900-909.