溃疡性结肠炎患者血浆MMP-2及TIMP-2测定的意义
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摘要
目的:研究溃疡性结肠炎(ulcerative colitis,UC)患者血浆中基质金属蛋白酶-2(matrix metalloproteinase-2,MMP-2)及其组织抑制因子-2(tissue inhibitor of metalloproteinase-2,TIMP-2)的表达水平,探讨其与UC的关系,进而研究血浆中MMP-2、TIMP-2作为诊断UC新的生物学指标的可行性和有效性。
方法:收集26例由临床表现、肠镜及病理证实为UC的患者作为实验组。其中男11例,女15例,年龄18～76岁,平均年龄45.7±17.0岁;全结肠9例,右半结肠2例,直乙状结肠11例,直肠4例;并根据临床表现及病理学诊断将UC患者分为轻型组11例,其中男6例,女5例,平均年龄43.4±16.5岁:中-重型组15例(其中,中型12例,重型3例,因重型患者较少,故并到中型一起统计),其中男6例,女9例,平均年龄47.1±14.8岁。同时,采集18例正常人的外周血作为对照组,其中男10例,女8例,年龄21～70岁,平均年龄49.0±19.1岁。采用酶联免疫检测技术(ELISA法)对血浆中MMP-2、TIMP-2的表达水平进行检测,并对二者与临床病情之间的关系进行统计学分析。
结果:
1、UC患者血浆MMP-2明显高于正常对照组(9.706±2.624 ng/ml Vs 6.608±1.678 ng/ml,P<0.05),UC患者血浆TIMP-2水平和正常对照组相比无显著性差异(6.13±2.317 ng/ml Vs 5.508±3.05 ng/ml,P>0.05)。
2、轻型UC患者血浆MMP-2水平比正常对照组明显升高( 8.161±1.943 ng/ml Vs 6.608±1.678 ng/ml,P <0.05),中-重型比轻型及正常对照组明显升高(11.030±2.441 ng/ml Vs 8.161±1.943 ng/ml Vs 6.608±1.678 ng/ml,P <0.05),而血浆中TIMP-2在轻型与中-重型患者及正常对照组中无统计学差异(6.374±2.009 ng/ml Vs 5.920±2.608 ng/ml Vs 5.509±3.052 ng/ml,P>0.05)。
3、血浆MMP-2水平与UC患者病情呈正相关(相关系数r为0.692,P= 0.000<0.05 ) ,即病情越重血浆MMP-2水平越高;而血浆TIMP-2及MMP-2/TIMP-2与UC患者病情均无相关性(P>0.05)。
结论:血浆MMP-2水平与UC患者病情严重程度存在相关性;MMP-2可能在UC的发病过程中起重要作用;血浆MMP-2可能作为临床诊断UC新的简单易行的生物学指标,为临床上UC的诊断提供一定的理论依据。
Objective: This study was aimed to investigate the relationship of levels of plasma matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2(TIMP-2) in patients with ulcer- ative colitis (UC) , and to identify whether or not MMP-2 and TIMP-2 expressed in plasma could be used as new,simple and useful biological parameters in diagnosing UC.
Methods: Twenty-six patients with UC confirmed by colonoscopy and biopsy were enrolled in the study. Among these patients,11 were males and 15 were females with their age ranged from 18 to 76 years and averaged 45.7±17.0 years. There were 9 patients with pan-colonic lesions, 2 with hemi-colonic lesions, 11 with recto-sigmoidal lesions, and 4 with rectal-lesions. Based on the clinical manifestations and biopsy, 11 patients were classified into mild type,among these patients,6 were males and 5 were females with their averaged 43.4±16.5 years; 15 patients were classified into moderate to severe type, among these patients,6 were males and 9 were females with their averaged 47.1±14.8 years. Meanwhile, 18 normal subjects were selected as controls; 10 of them were males and 8 of them were females with their age ranged from 21 to 70 years and averaged 49.0±19.1 years. Venous blood samples were collected from the UC groups and control groups. ELISA assay was used to measure their plasma levels.Statistical analysis was carried out to investigate the correlations of MMP-2 and TIMP-2 between the UC groups and control groups and their relationships with the severity of clinical symptoms of the patients.
Results: 1.The plasma level of MMP-2 was significantly higher in patients with UC than in normal controls (9.706±2.624 ng/ml VS 6.608±1.678 ng/ml,P < 0.05), but the plasma levels of TIMP-2 was found no significant difference between UC and control groups(6.13±2.317 ng/ml Vs 5.508±3.05 ng/ml,P>0.05);
2.The plasma level of MMP-2 was higher in mild groups than that in controls(8.161±1.943 ng/ml Vs 6.608±1.678 ng/ml, P<0.05);the plasma level of MMP-2 was higher in moderate to severe groups than that in mild and control groups(11.030±2.441 ng/ml Vs 8.161±1.943 ng/ml Vs 6.608±1.678 ng/ml,P<0.05);But that of TIMP-2 wasn’t(6.374±2.009 ng/ml Vs 5.920±2.608 ng/ml Vs 5.509±3.052 ng/ml,P>0.05).
3.Plasma level of MMP-2 was positively correlated with the severity of the disease(r=0.692,P = 0.000<0.05), but that of TIMP-2 and MMP-2/ TIMP-2 weren’t(P>0.05).
Conclusion: Plasma level of MMP-2 is correlated with the severity of clinical symptoms in patients with UC; MMP-2 may play an important role in the pathogenesis of ulcerative colitis;Plasma MMP-2 could be considered as a simple biological parameter for the severity and clinical diagnosis of UC.
方法:收集26例由临床表现、肠镜及病理证实为UC的患者作为实验组。其中男11例,女15例,年龄18～76岁,平均年龄45.7±17.0岁;全结肠9例,右半结肠2例,直乙状结肠11例,直肠4例;并根据临床表现及病理学诊断将UC患者分为轻型组11例,其中男6例,女5例,平均年龄43.4±16.5岁:中-重型组15例(其中,中型12例,重型3例,因重型患者较少,故并到中型一起统计),其中男6例,女9例,平均年龄47.1±14.8岁。同时,采集18例正常人的外周血作为对照组,其中男10例,女8例,年龄21～70岁,平均年龄49.0±19.1岁。采用酶联免疫检测技术(ELISA法)对血浆中MMP-2、TIMP-2的表达水平进行检测,并对二者与临床病情之间的关系进行统计学分析。
结果:
1、UC患者血浆MMP-2明显高于正常对照组(9.706±2.624 ng/ml Vs 6.608±1.678 ng/ml,P<0.05),UC患者血浆TIMP-2水平和正常对照组相比无显著性差异(6.13±2.317 ng/ml Vs 5.508±3.05 ng/ml,P>0.05)。
2、轻型UC患者血浆MMP-2水平比正常对照组明显升高( 8.161±1.943 ng/ml Vs 6.608±1.678 ng/ml,P <0.05),中-重型比轻型及正常对照组明显升高(11.030±2.441 ng/ml Vs 8.161±1.943 ng/ml Vs 6.608±1.678 ng/ml,P <0.05),而血浆中TIMP-2在轻型与中-重型患者及正常对照组中无统计学差异(6.374±2.009 ng/ml Vs 5.920±2.608 ng/ml Vs 5.509±3.052 ng/ml,P>0.05)。
3、血浆MMP-2水平与UC患者病情呈正相关(相关系数r为0.692,P= 0.000<0.05 ) ,即病情越重血浆MMP-2水平越高;而血浆TIMP-2及MMP-2/TIMP-2与UC患者病情均无相关性(P>0.05)。
结论:血浆MMP-2水平与UC患者病情严重程度存在相关性;MMP-2可能在UC的发病过程中起重要作用;血浆MMP-2可能作为临床诊断UC新的简单易行的生物学指标,为临床上UC的诊断提供一定的理论依据。
Objective: This study was aimed to investigate the relationship of levels of plasma matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2(TIMP-2) in patients with ulcer- ative colitis (UC) , and to identify whether or not MMP-2 and TIMP-2 expressed in plasma could be used as new,simple and useful biological parameters in diagnosing UC.
Methods: Twenty-six patients with UC confirmed by colonoscopy and biopsy were enrolled in the study. Among these patients,11 were males and 15 were females with their age ranged from 18 to 76 years and averaged 45.7±17.0 years. There were 9 patients with pan-colonic lesions, 2 with hemi-colonic lesions, 11 with recto-sigmoidal lesions, and 4 with rectal-lesions. Based on the clinical manifestations and biopsy, 11 patients were classified into mild type,among these patients,6 were males and 5 were females with their averaged 43.4±16.5 years; 15 patients were classified into moderate to severe type, among these patients,6 were males and 9 were females with their averaged 47.1±14.8 years. Meanwhile, 18 normal subjects were selected as controls; 10 of them were males and 8 of them were females with their age ranged from 21 to 70 years and averaged 49.0±19.1 years. Venous blood samples were collected from the UC groups and control groups. ELISA assay was used to measure their plasma levels.Statistical analysis was carried out to investigate the correlations of MMP-2 and TIMP-2 between the UC groups and control groups and their relationships with the severity of clinical symptoms of the patients.
Results: 1.The plasma level of MMP-2 was significantly higher in patients with UC than in normal controls (9.706±2.624 ng/ml VS 6.608±1.678 ng/ml,P < 0.05), but the plasma levels of TIMP-2 was found no significant difference between UC and control groups(6.13±2.317 ng/ml Vs 5.508±3.05 ng/ml,P>0.05);
2.The plasma level of MMP-2 was higher in mild groups than that in controls(8.161±1.943 ng/ml Vs 6.608±1.678 ng/ml, P<0.05);the plasma level of MMP-2 was higher in moderate to severe groups than that in mild and control groups(11.030±2.441 ng/ml Vs 8.161±1.943 ng/ml Vs 6.608±1.678 ng/ml,P<0.05);But that of TIMP-2 wasn’t(6.374±2.009 ng/ml Vs 5.920±2.608 ng/ml Vs 5.509±3.052 ng/ml,P>0.05).
3.Plasma level of MMP-2 was positively correlated with the severity of the disease(r=0.692,P = 0.000<0.05), but that of TIMP-2 and MMP-2/ TIMP-2 weren’t(P>0.05).
Conclusion: Plasma level of MMP-2 is correlated with the severity of clinical symptoms in patients with UC; MMP-2 may play an important role in the pathogenesis of ulcerative colitis;Plasma MMP-2 could be considered as a simple biological parameter for the severity and clinical diagnosis of UC.
引文
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2. Heuschkel RB, MacDonald TT, Monteleone G et al. Imbalance of stromelysin1 and TIMP1 in the mucosal lesions of children with inflammatory bowel disease Gut, 2000; 47:57-62.
3. von Lampe B, Barthel B, Coupland SE et al. Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease Gut 2000; 47:63-73
4. Wang YD, Yan PY. Expression o f matrix metalloproteinase-1 and tissue inhi- bitor of metalloproteinase-1 in ulcerative colitis. World J Gastroenterol 2006; 12:6050-6053
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8. MeijerMJ,Mieremet OMA, van der Zon AM, et al. Increased mucosal matrix metalloproteinase-1, -2, -3 and -9 activity in patientswith inflammatory bowel disease and the relation with Crohn’s disease phenotype Dig LiverDis, 2007; 39(8):733-739
9.陈锡美,刘文滨,陈文骏等.溃疡性结肠炎患者基质金属蛋白酶-2,9和抑制因子-1,2的表达及其意义临床内科杂志2003;20(7):384-386
10.缪应雷,欧阳钦,段丽平等.基质金属蛋白酶1、基质金属蛋白酶2和基质金属蛋白酶3在溃疡性结肠炎患者肠黏膜的表达临床内科杂志2005;22(10):682-684
11. Pirila E, RamamurthyNS, Sorsa T et al. Gelatinase A (MMP2), collagenase-2 (MMP-8), and laminin-5 gamma2-chain expression inmurine inflammatory bowel disease ( ulcerative colitis) Dig DisSci 2003;48(1):93-98.
12. Zucker S, Lysik RM, Zarrabi MH et al. M(r)92,000 type IV collagenase isincreased in plasma of patients with colon cancer and breast cancer. Cancer Res 1993;53: 140-146
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16. Holten-Andersen MN, Christensen IJ, Nielsen HJ et al. Total levels of tissue inhibitor of metalloproteinases 1 in plasma yield high diagnostic sensitivity and specificity in patients with colon cancer. Clin Cancer Res 2002;8:156-164
17.王英德,谭小燕,张可.溃疡性结肠炎患者血浆MMP-1与TIMP-1测定的意义.世界华人消化杂志.2008;16(29):3351-3353
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9.陈锡美,刘文滨,陈文骏等.溃疡性结肠炎患者基质金属蛋白酶-2,9和抑制因子-1,2的表达及其意义临床内科杂志2003;20(7):384-386
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11. Pirila E, RamamurthyNS, Sorsa T et al. Gelatinase A (MMP2), collagenase-2 (MMP-8), and laminin-5 gamma2-chain expression inmurine inflammatory bowel disease ( ulcerative colitis) Dig DisSci 2003;48(1):93-98.
12. Zucker S, Lysik RM, Zarrabi MH et al. M(r)92,000 type IV collagenase isincreased in plasma of patients with colon cancer and breast cancer. Cancer Res 1993;53: 140-146
13. Kai H, Ikeda H, Yasukawa H et al. Peripheral blood levels of matrix metallo- proteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 1998; 32:368-372
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16. Holten-Andersen MN, Christensen IJ, Nielsen HJ et al. Total levels of tissue inhibitor of metalloproteinases 1 in plasma yield high diagnostic sensitivity and specificity in patients with colon cancer. Clin Cancer Res 2002;8:156-164
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22. Brinckerhoff CE, Matrisian LM. Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 2002; 3:207-214
23. Oberg A, Hoyhtya M, Tavelin B et al.Limited value of preoperative serum analyses of matrix metalloproteinases(MMP-2, MMP-9) and tissue inhibitors of matrix metalloproteinases (TIMP-1, TIMP-2) in colorectal cancer.Anticancer Res 2000; 20: 1085-1091
24. Tutton MG, George ML, Eccles SA et al. Use of plasma MMP-2 and MMP-9 levels as a surrogate for tumour expression in colorectal cancer patients. Int J Cancer 2003; 107:541-550
25. Breyholz HJ , Wagner S , Levkau B et al. A(18)F-radiola-beled analogue of CGS27023A as a potential agent for assessment of matrix-metalloproteinase activity in vivo Q J Nucl Med Mol Imaging ,2007;51(1):24-32.
26. Vaday GC, Schol H, RahatMA, et al. Tranforming growth factorbeta suppresses tumor nerosis factor alphauinduced matrixmetallop roteinase-9 expression in monoeytes J Leukoc Biol, 2003; 69(4):6131
27. Ottino P, Taheri F, Bazan HF. Platelet-activating factor induces the gene exp- ression of TIMP-1, 2, and PAI-1: imbalance between the gene expression of MMP-9 and TIMP-1 and -2. Exp Eye Res,2002; 74(3):393-402.
28.刘友良,黄平.基质金属蛋白酶-2与肿瘤关系的研究进展.现代肿瘤医学2006; 14(1):109-111.
29. Chow AK, Cena J, Schulz R. Acute actions and novel targets of matrix metallo- proteinases in the heart and vasculature. Br J Pharmacology,2007; 152:189- 205.
30.毛梅,曾群丽,余爱荣.基质金属蛋白酶-2在肺癌患者血清中的表达及临床意义.新乡医学院学报, 2006;23(2):151-153.
31.侯元婕,薛克修.基质金属蛋白酶及其抑制因子与组织纤维化的研究进展.新乡医学院学报2006;23(2):204-206.
32. RaptiM, KnaüperV,Murphy G et al. Characterization of the AB Loop Region of TIMP-2: involvement in Pro-MMP-2 Activation. J B iol Chem , 2006, 281(33): 23386-23394.
33.葛成华,王世伟,叶古祥,潘芳芳等.胃癌病人之血浆金属蛋白酶和组织抑制物水平及其临床意义.外科理论与实践.2005;10(5):429
34. Murawaki Y, Yamada S , Ikuta Y et al. Clinical usefulness of serum matrix metalloproteinase-2 concentration in patients with chronic virul liver disease J Hepatol 1999;30(6):1090-1098
35. Gohji K, Fujimoto N , Hara I et al. Serum matrix metalloproteinase-2 and its density in men with prostate cancer as a new predictor of disease extersion Int J Cancer 1998;79(1):96-101
36. Ivanov PA , Grishin AV , Syromiatnikova ED et al. The dynamics of blood serum middle-molecule peptides in the prognosis of the course of acute pancreatitis. El’kov AN Vestn Khir Im I Grek ,1999;158(6):32-35
37. Hammani K,Blakis A ,Morsette D et al. Structure and characterization of the human tissue inhibitor of metalloproteinases-2 gene. J BiolChem ,1996 ,271: 25498-25505.