艾塞那肽诱发大鼠胰腺组织病变的实验研究

目的 探讨艾塞那肽诱发大鼠胰腺组织病变的可能机制.方法 SD雄性大鼠30只按完全随机法分为艾塞那肽组、糖尿病组和对照组,每组10只.高糖、高脂喂养及腹腔注射链脲佐菌素（35 mg/kg体质量）方法诱导大鼠糖尿病模型,艾塞那肽组和糖尿病组每天2次皮下注射艾塞那肽5 μg/kg体质量,对照组皮下注射等容积生理盐水,实验周期为10周.大鼠处死后取胰腺组织,常规病理检查.免疫组化法检测胰腺组织α-平滑肌肌动蛋白（α-SMA）和Ⅲ型胶原蛋白表达,ELISA法检测胰腺组织基质金属蛋白酶2（MMP-2）和MMP-9含量.结果 对照组大鼠胰腺组织未见病理变化,艾塞那肽组大鼠胰腺组织出现慢性炎性改变,糖尿病组大鼠胰腺病变程度较艾塞那肽组严重,3组胰腺病理评分依次增高（P＜0.05）.对照组、艾塞那肽组和糖尿病组胰腺组织的MMP-2含量分别为（186.98±23.24）、（306.07±59.82）、（365.08±89.55） μg/L;MMP-9含量分别为（49.37±7.08）、（67.24±14.73）、（87.37±13.39） μg/L.艾塞那肽组和糖尿病组均显著高于对照组（P值均＜0.05）,但艾塞那肽组和糖尿病组间的差异无统计学意义.对照组、艾塞那肽组和糖尿病组大鼠高倍视野内胰腺组织的α-SMA阳性表达细胞数分别为（13.4±6.0）、（29.5±8.8）、（79.3±27.2）个,Ⅲ型胶原蛋白阳性表达细胞数分别为（10.6±4.9）、（29.3±13.0）、（56.0±27.2）个.艾塞那肽组阳性细胞数均显著多于对照组,糖尿病组阳性细胞数又显著多于艾塞那肽组（P值均＜0.05）.结论 长期皮下注射艾塞那肽可能激活胰腺星状细胞,表达α-SMA和Ⅲ型胶原蛋白,分泌MMP-2、MMP-9,诱发胰腺组织慢性炎性改变.

The experimental study of pancreatic tissue lesion induced by Exenatide

Objective To explore the mechanism of Exenatide-induced rat pancreatic tissue lesion.Methods Thirty SD male rats were divided into three groups according to complete random design,and each group had 10 rats,namely Exenatide group,diabetes-model group and control group.Diabetes-model rats were induced by streptozotocin （STZ,35mg/kg） and high-sugar and high-fat diet.The Exenatide group and diabetes group were subcutaneously administered with Exenatide at a dose of 5 μg/kg twice a day.The control group was treated with same amount of saline.Ten weeks later,all the rats were sacrificed and the pancreatic tissues were harvested for routine pathological examination.Immunohistochemical method was used to detect the expression of α-smooth muscle actin （α-SMA） and type Ⅲ collagen protein in pancreatic tissue,and ELISA was applied to measure the expression of matrix metalloprotei-nase-2 （MMP-2） and MMP-9 in pancreatic tissue.Results In control group,there was no pathological change in pancreatic tissue.In Exenatide group,chronic inflammatory changes were observed; and the degree of inflammatory changes were much severe in diabetes group,and the pathological scores were gradually increased in the 3 groups （P 〈0.05）.The expressions of MMP 2 in pancreatic tissue in control group,Exenatide group,diabetes group were （186.98 ± 23.24）,（306.07 ± 59.82）,（365.08 ± 89.55） μg/L,and the expressions of MMP-9 were （49.37 ± 7.08）,（67.24 ±14.73）,（87.37 ±13.39）μg/L.The values were significantly higher in Exenatide group and diabetes group than those in control group （P 〈 0.05）,but the difference between the two groups was not statistically significant.The numbers of α-SMA positive cells per high power field were （13.4 ± 5.97）,（29.5 ± 8.80）,（79.3 ± 27.23） in control group,Exenatide group,diabetes group,and the numbers of type Ⅲ collagen positive cells were （10.6 ± 4.93）,（29.3 ± 12.95）,（56.0 ± 27.21）.The values were significantly higher in Exenatide group than those in control group,and the values were significantly higher in diabetes group than those in Exenatide group （P 〈 0.05）.Conclusions Long-term subcutaneous injection of Exenatide may activate pancreatic stellate cells and cause expression of α-SMA,Ⅲ collagen protein,and MMP-2,MMP-9,then induce chronic inflammatory changes.