APG治疗糖尿病难治性皮肤溃疡对创面肉芽组织中MMP-1、MMP-9及TIMP-1水平的影响

目的探讨自体富血小板凝胶(APG)治疗糖尿病难治性皮肤溃疡过程中,溃疡肉芽组织中基质金属蛋白酶(MMP)-1、-9及基质金属蛋白酶抑制因子-1(TIMP-1)的动态变化。方法 86例糖尿病皮肤溃疡患者随机分为标准治疗组(单用溃疡标准治疗)或APG治疗组(标准治疗基础上加APG治疗)。APG组治疗前和治疗后3、6、9、15d及标准治疗组治疗前和治疗后6、15d时采集创面肉芽组织,其中21例患者完整获取观察各时间点肉芽组织纳入最后分析,APG组12例,标准治疗组9例。用酶联免疫法检测肉芽组织中MMP-1、MMP-9和TIMP-1浓度,同时观察溃疡愈合情况。结果 APG治疗组溃疡面积在各观察时间点较治疗前缩小(P<0.05);该组肉芽组织MMP-1浓度呈现波动变化,在治疗后第15d时降至最低(vs.6d,P<0.05);MMP-9从治疗后第3d起逐渐降低,但各时点与治疗前相比,差异均无统计学意义;TIMP-1在治疗后第3d开始增高,第6d达到最高(P<0.05);MMP-9/TIMP-1比值在治疗后的第6、15d均较治疗前下降(P<0.01)。标准治疗组溃疡面积在治疗后第15d时较治疗前及治疗后第6d缩小(P<0.05);该组肉芽组织MMP-1浓度第6d明显升高(P<0.05),于第15d降低但仍高于APG组(P<0.05);MMP-9浓度第15d时较治疗前降低(P<0.05);TIMP-1的浓度治疗前后差异均无统计学意义;MMP-9/TIMP-1比值第15d较治疗前降低(P<0.05)。MMP-9/TIMP-1比值与溃疡面积大小呈正相关(r=0.353,P<0.05)。结论 APG治疗可降低糖尿病难治性皮肤溃疡肉芽组织中MMPs的浓度,同时提高TIMPs浓度,进而改善局部MMPs-TIMPs平衡;MMP-9/TIMP-1比值是影响糖尿病难治性皮肤溃疡愈合的相关因素。

Dynamic Changes of MMP-1, MMP-9 and TIMP-1 in the Refractory Diabetic Dermal Ulcers Treated by AutologousPlatelet-rich Gel

Objective To investigate the dynamic changes of matrix metalloproteinase-1,-9(MMP-1,MMP-9) and tissue inhibitor of metalloproteinase-l(TIMP-1) in the refractory diabetic dermal ulcers treated with autologous platelet-rich gel(APG).Methods 86 patients with nonhealing diabetic dermal ulcers were randomly assigned to two groups treated with standard procedures and APG(standard care plus topic application of autologous platelet-rich gel).The granulation tissues were collected at d0,d3,d6,d9,and d15 in patients in the APG group and at d0,d6,d15 in patients in the standard care group.The areas of ulcers were measured.The protein levels of MMP-1,MMP-9 and TIMP-1 in the tissues were determined with ELISA.The ratio of MMP-9/TIMP-1 and its relationship with the areas of ulcers were examined.Results The areas of ulcers of patients in the APG group decreased significantely(vs.do,P<0.05).The concentrations of MMP-1 in the granulation tissues of patients treated with APG fluctuated and reached the lowest level at d15(vs.d6,P<0.05).The concentrations of MMP-9 in the patients treated with AGP decreased from d3 to d15,but without statistical significance compared with d0(P>0.05).The concentrations of TIMP-1 in the patients treated with AGP increased from d3 and reached the peak at d6(P<0.05).The ratio of MMP-9/TIMP-1 at both d6 and d15 decreased significantly compared with d0(P<0.05) in the patients treated with AGP.The areas of ulcers in the patients with standard care decreased significantly at d15(vs.d6,P<0.05).The concentrations of MMP-1 reached the peak at d6(P<0.05) and then decreased in the patients with standard care but was still higher than the patients treated with APG(P<0.05).The concentrations of MMP-9 decreased significantly at d 15 compared with d0 in the patients treated with standard care(P<0.05),but the change of TIMP-1 was not significant.The ratio of MMP-9/TIMP-1 in the p atients with standard care decreased at d15 compared with the d0(P<0.05). The ratio of MMP-9/TIMP-1 was positively correlated with the areas of ulcers ( r=0.353,P<0.05).Conclusion Topical application of APG might redress the proteolytic imbalance of refractory diabetic dermal ulcers by decreasing the concentration of MMPs and increasing that of TIMPs in granulatio n tissues.The ratio of MMP-9/TIMP-1 is a predictor of poor healing of refract ory diabetic dermal ulcers.