Fingolimod对小鼠慢性胰腺纤维化的抑制作用

Inhibitory Effect of Fingolimod in Pancreatic Fibrosis

目的:观察新型免疫抑制剂Fingolimod(FTY720)对雨蛙素致小鼠慢性胰腺纤维化的治疗作用。方法:健康雄性C57BL/6小鼠30只,随机分为对照组、模型组和FTY720治疗组。模型组和治疗组腹腔注射雨蛙素,50μg·kg^(-1)·次^(-1),1周3次,连续6周;治疗组于第5周开始注射FTY720,1 mg·kg^(-1)·d^(-1),持续2周;对照组腹腔注射等量的生理盐水。于第7周第1天留取胰腺组织,行HE染色和苦味酸-天狼星红染色,分别于光镜和偏振光显微镜下观察病理改变和评分,并用免疫组织化学染色法观察α平滑肌肌动蛋白(α-SMA)、CD3、FOXP3表达情况。结果:模型组病理评分中,腺泡萎缩为2.52±0.36,炎细胞浸润为3.42±0.31,纤维化程度为3.25±0.42,显著高于对照组的病理评分。模型组α-SMA表达为25.33±5.64,CD3表达为68.83±8.38,FOXP3表达为34.83±6.85,均显著高于对照组(分别为0.33±0.52,1.83±0.75,1.33±0.82)。治疗组病理评分中,腺泡萎缩为1.69±0.27,炎细胞浸润为2.34±0.33,纤维化程度为2.19±0.35,均较模型组明显减少。治疗组胰腺组织中α-SMA表达为12.33±2.58,CD3为25.00±4.93,FOXP3为17.33±4.41,也明显低于模型组。结论:FTY720能明显减少雨蛙素所致的T淋巴细胞浸润和调节性T细胞数量,在一定程度上减轻胰腺间质胶原的表达,从而抑制胰腺纤维化程度。

Objective To observe the inhibitory effect of Fingolimod（FTY720） in cerulein induced pancre-atic fibrosis.Methods Thirty male C57BL/6 mice were divided into control group, model group and FTY720 treated group（10 animals per group）. The model mice and FTY720 treated mice were received repeated intraperi-toneal injection of cerulein for six weeks.The FTY720 group mice received intraperitoneal injection of FTY720（1 mg/kg/d） after the fourth week. The control group mice received saline injections. Seven weeks after the firstintraperitoneal injection of cerulein the pancreas was removed for pathological assessment of acinar atrophy, in-flammatory infiltration and fibrosis. The second part was stained with picricsirius red and observed by polarizedlight microscopy. The third part of pancreatic specimen was used to examine α-smooth muscle actin（α-SMA）,CD3 and FOXP3 expression by immunohistochemical method.Results Compared with control group, the pathological score in model group mice（ acinar atrophy 2.52±0.36 vs 0,inflammatory infiltration 3.42±0.31 vs0,fibrosis 3.25±0.42 vs 0） was higher and much more expression of collagen in model mice. The expression of α-SMA（25.33±5.64 vs 0.33±0.52）、CD3（68.83±8.38 vs 1.83±0.75）and FOXP3（34.83±6.85 vs 1.33±0.82）were all increased in model mice. Compared with model group, the pathological score in FTY720 group（acinaratrophy 1.69±0.27 vs 2.52±0.36 inflammatory infiltration 2.34±0.33 vs 3.42±0.31,fibrosis 2.19±0.35 vs3.25±0.42） was lower and the expression of collagenwas decreased. The expression of α-SMA（12.33 ±2.58 vs 25.33±5.64）、CD3（25±4.93 vs 68.83±8.38）and FOXP3（17.33±4.41 vs 34.83±6.85）were all decreased markedly in FTY720 group mice.Conclusion FTY720 could reduce the T lymphocytes infiltration and regulatory T cell quantity, thus alleviate the accumulation of collagen in pancrease. FTY720 inhibit pancreatic fibrosis may be related to these.