MMP-2抑制剂治疗自身免疫性心肌炎大鼠的实验研究

Experimental study of MMP-2 inhibitor treatment of experimental autoimmune myocarditis in Lewis rats

目的:观察基质金属蛋白酶-2(MMP-2)抑制剂TISAM对实验性自身免疫性心肌炎(EAM)Lewis大鼠模型的治疗效果,并探索可能的治疗机理。方法:口服5 mg/kg TISAM,每日一次,连续14 d治疗EAM Lewis大鼠动物。根据治疗方案不同,分3组,分别为早、中和晚期治疗组(n=20)。治疗结束后,处死动物,心脏取材,进行心肌炎症分级、心肌胶原纤维含量,心肌巨噬细胞和T细胞浸润,MMP-2和MMP-9的mRNA表达,以及明胶酶活性测定。结果:TISAM早期治疗(在模型建立同时开始治疗,持续14 d)无效,中、后期治疗(在模型建立后第7～14天开始治疗,持续14 d)有效。在治疗有效方案中,治疗组与对照组相比,心肌炎症级别下降,心肌间质纤维化级别下降,巨噬细胞和T淋巴细胞浸润数目减少,MMP-2 mRNA表达降低,明胶酶活性降低。结论:MMP-2抑制剂抑制EAM中期的病理发展过程,其机制可能与降低心肌炎症细胞浸润,延缓心肌间质纤维化,从转录水平降低MMP-2 mRNA的表达,同时从蛋白水平降低明胶酶活性表达有关。

Objective： To investigate the inhibitor of matrix metalloproteinase-2 （MMP-2） （2R）-2-[ 5-[4-[ ethyl-methylamino] phenyl [ thiophene-2-sulfonylamino]-3-methylbutyric acid （TISAM） therapeutic effect on experimental autoimmune myocarditis （EAM） in lewis rats. Methods： Treatment protocol of oral administration of 5mg/kg TISAM once a day for 14 days was performed on EAM Lewis rats. EAM lewis rats were divided into 3 groups：treatment in early, middle and later stage respectively（ n = 20）. After experiment at the designate time peint, the rats were euthanatized and hearts were harvested. Cardiac inflammatory score, fibrosis score and content, and infiltration of macrophages and T lyminflammatory score, fibrosis score and content, and infiltration of macrophages and T lymphocytes, message RNA （mRNA） expression of matrix metalloproteinase （MMP） -2 and MMP-9 and protein activity of gelatinase were determined. Results： TISAM treatment in early phase was invalid （treatment started from the creation of the model）, treatment in middle and later phase was effective （treatment started from 7 and 14 day after the creation of the model）. Conclusion： Inhibitor of MMP-2 can block ventricular remodeling in middle stage in EAM Lewis rats. The mechanism maybe alleviate the inflammatory cell cardiac infiltration, decrease the mRNA expression of MMP-2 at transcript level and downregulate gelatinase activity at protein level.