姜黄素对胃黏膜上皮异型增生小鼠的胃组织形态和炎症微环境的影响

Effect of Curcumin on Gastric Tissue Morphology and Inflammatory Microenvironment in Mice with Gastric Epithelial Dysplasia

目的观察姜黄素对胃黏膜上皮异型增生(gastric epithelia dysplasia,GED)小鼠的胃组织形态及炎症微环境的影响,评估姜黄素对GED的预防和缓解作用。方法设正常对照组、模型组、姜黄素低、中、高剂量组和阳性对照组,除正常对照组外,其余各组均采用复合因素造模法造模,诱导GED动物模型。造模8周后,姜黄素低、中、高剂量组及阳性对照组分别给予姜黄素38、75、150 mg·kg^(-1)和维霉素350 mg·kg^(-1)进行干预,持续8周。实验期末,检测各实验组小鼠胃蛋白酶原(PGⅠ)、干扰素-γ(IFN-γ)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)含量及磷酸化酪氨酸激酶2(p-JAK2)、信号转导与转录激活因子3(p-STAT3)、细胞周期蛋白D1(cyclin D1)相对表达量。苏木素-伊红(hematoxylin-eosin,HE)染色和增殖细胞核抗原(proliferating cell nuclear antigen,PCNA)抗体免疫组化染色,观察各组小鼠胃黏膜组织形态及细胞增殖情况,对GED和炎症细胞浸润进行组织病理学评分,计算细胞增殖指数(proliferation index,PI)。结果与正常对照组比较,模型组小鼠血清PGⅠ浓度下降,胃组织中IL-1β、IFN-γ、IL-6含量上升(P<0.05),GED和胃黏膜炎症细胞浸润评分及PI均上升(P<0.01),组织病理学观察发现胃黏膜出现异型增生、炎症细胞浸润等改变,细胞增殖活性增强,p-JAK2、p-STAT3、Cyclin D1表达上调(P<0.05)。与模型组比较,姜黄素中、高剂量组血清PG1浓度上升,胃组织中炎症因子IFN-γ、IL-6含量降低(P<0.05),GED和胃黏膜炎症细胞浸润评分及PI均下降(P<0.05或0.01),胃黏膜异型增生、炎症细胞浸润缓解,细胞增殖活性受到抑制,p-JAK2、p-STAT3、Cyclin D1表达下调(P<0.05)。姜黄素低剂量组p-JAK2蛋白表达量下调,高剂量组IL-1β下降(P<0.05)。结论姜黄素对小鼠GED有预防和缓解作用,可以改善GED小鼠胃黏膜的组织形态,其作用机制可能与下调JAK2/STAT3/Cyclin D1通路的信号转导,抑制细胞过度增殖有关。

OBJECTIVE To observe the effects of curcumin on the gastric tissue morphology and inflammatory microenvironment in mice with gastric epithelia dysplasia(GED),and to evaluate the preventive and therapeutic effects of curcumin on GED.METHODS Normal control group,model group,low,medium,and high dose groups of curcumin,and positive control group were set up.Except for the normal control group,all other groups were induced to establish GED animal models using a compound factor modeling method.After 8 weeks of modeling,the low,medium,and high dose groups of curcumin and the positive control group were respectively given curcumin at doses of 38,75,150 mg·kg^(-1)and vitacoenzyme 350 mg/kg for intervention,continued for 8 weeks.At the end of the experiment,the gastric levels of pepsinogen PGⅠ,IFN-γ,IL-1β,IL-6,and the relative expression levels of p-JAK2,p-STAT3,Cyclin D1 in each experimental group were detected.HE staining and PCNA antibody immunohistochemistry were performed to observe the gastric mucosal tissue morphology and cell proliferation in each group.The pathological scores of GED and inflammatory cell infiltration were evaluated,and the proliferation index(PI)was calculated.RESULTS Compared with the normal control group,the serum concentration of PGⅠin mice in the model group decreased,while the levels of IL-1β,IFN-γ,and IL-6 in gastric tissue increased(P<0.05).The scores of GED and gastric mucosal inflammatory cell infiltration,as well as the proliferation index(PI),all increased(P<0.01).Histopathological observations revealed changes such as epithelial dysplasia and inflammatory cell infiltration in the gastric mucosa,enhanced cell proliferation activity,and upregulation of p-JAK2,p-STAT3,and Cyclin D1 expression(P<0.05).Compared with the model group,the medium and high dose groups of curcumin showed an increase in serum PG1 concentration,a decrease in the inflammatory factors IFN-γand IL-6 levels in gastric tissue(P<0.05),a decrease in GED and gastric mucosal inflammatory cell infiltration scores,as well as PI(P<0.05 or 0.01).The curcumin treatment alleviated gastric mucosal dysplasia and inflammatory cell infiltration,inhibited cell proliferation activity,and downregulated the expression of p-JAK2,p-STAT3,and Cyclin D1(P<0.05).In the low dose group of curcumin,the expression of p-JAK2 protein was downregulated,and in the high dose group,IL-1βdecreased(P<0.05).CONCLUSION Curcumin has a preventive and alleviating effect on the epithelial dysplasia of the gastric mucosa in mice,and can improve the tissue morphology of the gastric mucosa in GED mice.Its mechanism of action may be related to the downregulation of the JAK2/STAT3/Cyclin D1 pathway signaling,inhibiting excessive cell proliferation.