MMP-1、9及TIMP-1、EGF在慢性皮肤溃疡治疗前后水平变化
摘要
目的探究在慢性皮肤溃疡治疗过程中肉芽组织内基质金属蛋白酶(MMP)-1、MMP-9、MMP抑制剂(TIMP)-1和表皮生长因子(EGF)的动态变化过程。方法慢性难愈性皮肤溃疡患者64例,随机分标准组和珠香散组。在治疗前和治疗后第7、14天收集肉芽组织,采用酶联免疫法检测肉芽组织中MMP-1、MMP-9、TIMP-1和EGF的浓度,同时观察皮肤溃疡患者的愈合情况。结果珠香散组和标准组在经过治疗后皮肤溃疡面积逐渐缩小,在治疗前和治疗后7、14 d的三个时间节点上的溃疡面积差异显著(P<0. 05)。在治疗后14 d,与珠香散组对比,标准组肉芽组织中MMP-1浓度较高,EGF浓度较低,差异显著(P<0. 05)。在珠香散组中,创面内肉芽组织中MMP-1蛋白水平在治疗后7、14 d明显高于治疗前; MMP-9蛋白水平呈逐渐下降的趋势,TIMP-1蛋白水平在经过珠香散治疗后开始升高,治疗前后差异有统计学意义(P<0. 05),经过珠香散治疗后,EGF浓度逐渐上升,且在治疗后7 d和14 d分别与治疗前对比差异有统计学意义(P<0. 05)。在标准组中,创面肉芽组织中MMP-1蛋白水平在治疗后7、14 d明显高于治疗前(P<0. 05)。治疗后7、14 d时MMP-9水平明显低于治疗前(P<0. 05);TIMP-1浓度在治疗后7 d时与治疗前对比差异明显(P <0. 05); EGF浓度在治疗前和治疗后7、14 d对比差异均明显(P<0. 05)。在治疗后7 d和治疗后14 d时,珠香散组中的MMP-9/TIMP-1比值较治疗前明显降低(P<0. 05);在标准组中,治疗后7 d和治疗后14 d时MMP-9/TIMP-1比值均下降,但只有治疗后14 d时的浓度与治疗前差异明显(P<0. 05)。通过Pearson相关性检验发现慢性皮肤溃疡患者的溃疡面积与创面肉芽组织中MMP-9/TIMP-1比值大小呈正相关关系(r=0. 375,P=0. 002 3),肉芽组织中EGF浓度与溃疡面积大小呈负相关关系(r=-0. 384,P=0. 001 7)。结论慢性皮肤溃疡在经过治疗后,创面肉芽组织中基质金属蛋白酶的浓度明显下降,TIMP-1浓度上升,MMP-9/TIMP-1比值和EGF的浓度是影响皮肤溃疡愈合的相关性因素。
引文
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14 Di Grazia A,Cappiello F,Imanishi A,et al.The frog skin-derived antimicrobial peptide esculentin-1a(1-21)NH2 promotes the migration of human Ha CaT keratinocytes in an EGF receptor-dependent manner:a novel promoter of human skin wound healing[J].PLoS One,2015;10(6):e0128663.
2 Saito S,Trovato MJ,You R,et al.Role of matrix metalloproteinases 1,2,and 9 and tissue inhibitor of matrix metalloproteinase-1 in chronic venous insufficiency[J].J Vasc Surg,2001;34(5):930-8.
3 Caimi G,Ferrara F,Montana M,et al.Behaviour of the plasma concentration of gelatinases and their tissue inhibitors in subjects with venous leg ulcers[J].Clin Hemorheol Microcirc,2015;60(3):309-16.
4 Bister V,Mkitalo L,Jeskanen L,et al.Expression of MMP-9,MMP-10 and TNF-alpha and lack of epithelial MMP-1 and MMP-26 characterize pyoderma gangrenosum[J].J Cutan Pathol,2007;34(12):889-98.
5 Guillemin Y,Le Broc D,Ségalen C,et al.Efficacy of a collagen-based dressing in an animal model of delayed wound healing[J].J Wound Care,2016;25(7):406-13.
6 Stefanov I,Pérez-Rafael S,Hoyo J,et al.Multifunctional enzymatically generated hydrogels for chronic wound application[J].Biomacromolecules,2017;18(5):1544-55.
7 Serra R,Buffone G,Falcone D,et al.Chronic venous leg ulcers are associated with high levels of metalloproteinases-9 and neutrophil gelatinase-associated lipocalin[J].Wound Repair Regen,2013;21(3):395-401.
8 Serra R,Gallelli L,Butrico L,et al.From varices to venous ulceration:the story of chronic venous disease described by metalloproteinases[J].Int Wound J,2017;14(1):233-40.
9 Li Z,Guo S,Yao F,et al.Increased ratio of serum matrix metalloproteinase-9 against TIMP-1 predicts poor wound healing in diabetic foot ulcers[J].J Diabetes Complications,2013;27(4):380-2.
10 Liu Y,Min D,Bolton T,et al.Increased matrix metalloproteinase-9predicts poor wound healing in diabetic foot ulcers[J].Diabetes Care,2009;32(1):117-9.
11 Mirastschijski U,Impola U,Jahkola T,et al.Ectopic localization of matrix metalloproteinase-9 in chronic cutaneous wounds[J].Hum Pathol,2002;33(3):355-64.
12 Dalton SJ,Mitchell DC,Whiting CV,et al.Abnormal extracellular matrix metabolism in chronically ischemic skin:a mechanism for dermal failure in leg ulcers[J].J Invest Dermatol,2005;125(2):373-9.
13 Burrow JW,Koch JA,Chuang HH,et al.Nitric oxide donors selectively reduce the expression of matrix metalloproteinases-8 and-9 by human diabetic skin fibroblasts[J].J Surg Res,2007;140(1):90-8.
14 Di Grazia A,Cappiello F,Imanishi A,et al.The frog skin-derived antimicrobial peptide esculentin-1a(1-21)NH2 promotes the migration of human Ha CaT keratinocytes in an EGF receptor-dependent manner:a novel promoter of human skin wound healing[J].PLoS One,2015;10(6):e0128663.