口服普萘洛尔对婴幼儿血管瘤MMP-2、MMP-9、TIMP-1、TIMP-2表达水平的影响

Effect of propranolol on expression of MMP-2,MMP-9,TIMP-1 and TIMP-2 in infantile hemangioma

目的研究口服普萘洛尔前后婴幼儿血管瘤病灶内MMP-2、MMP-9、TIMP-1、TIMP-2表达水平的影响。方法选择2010年5月至2011年12月来我院就诊、年龄≤3个月、血管瘤病灶位于肢体或隐蔽部位、家属要求手术治疗却具备单独口服普萘洛尔治疗条件、排除口服普萘洛尔禁忌证、先前未接受过其他任何相关治疗的病例作为研究对象,共39例。经过与家属沟通并征得其书面同意,先按口服普萘洛尔诊疗常规,口服用药前在局麻下夹取血管瘤体组织活检,后口服8周普萘洛尔[剂量:2 mg/(kg.d),分2次,每12小时用药],继而手术切除瘤体。采用免疫组化、实时荧光定量RT-PCR的方法,检测口服用药前后病灶组织内MMP-2、MMP-9、TIMP-1、TIMP-2表达水平的变化,计算口服用药前后病灶微血管密度(MVD)。结果免疫组化与实时荧光定量RT-PCR结果均提示,口服普萘洛尔后血管瘤病灶内MVD值明显减低且具有统计学意义(t=18.458,P<0.01),MMP-2、MMP-9表达水平较用药前明显减少(P<0.01),TIMP-1、TIMP-2表达水平明显增高(P<0.01)。且口服用药后上述4个因子免疫组化平均积分光密度、mRNA相对表达量变化与MVD值变化密切相关。结论普萘洛尔可下调血管瘤病灶内MMP-2、MMP-9的表达,上调TIMP-1、TIMP-2的表达,从而抑制新生血管的形成。

Objective To investigate the effect of propranolol on the expression of matrix metallopro- teinase 2 （ MMP-2）, matrix metalloproteinase 9 （ MMP-9 ）, tissue inhibitor of metalloproteinase 1 （ TIMP-1 ） and tissue inhibitor of metalloproteinase 2 （TIMP-2） in infantile hemangioma. Methods Thirty-nine patients （age≤3 months） with proliferative phase of hemangioma in our hospital from May, 2010 to December, 2010 were enrolled. The patients were treated with propranolol for 8 weeks after hemangioma biopsy, and then under- went surgery for hemangioma resection. The mRNA and protein expression levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 in hemangioma tissues were examined by quantitative real-time RT-PCR and immunohistochemical method, respectively, and the microvessel density （MVD） was calculated before and after propranolol treat- ment. Results The MVD in the hemangioma tissues decreased significantly after propranolol treatment （ P 〈 0.01 ）. The protein and mRNA expressions of MMP-2 and MMP-9 decreased significantly （P 〈0.01 ） , but the protein and mRNA expressions of TIMP-1 and TIMP-2 increased significantly after propranolol treatment （ P 〈 0.01 ）. The changes of MVD were closely correlated with the protein and mRNA expression levels of MMP-2, MMP-9; TIMP-1 and TIMP-2. Conclusion Propranolol can reduce proliferative hemangioma through down- regulating MMP-2 and MMP-9 expression and up-regulating TIMP-1 and TIMP-2 expression,