溃疡性结肠炎患者组织与血浆MMP-1与TIMP-1表达相关性的研究
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摘要
目的:分别检测溃疡性结肠炎(ulcerative colitis, UC)患者结肠组织( mRNA以及蛋白水平)与血浆中基质金属蛋白酶-1 (matrix metalloproteinase-1 ,MMP-1)及其组织抑制因子-1 (tissue inhibitors of matrix metallproteinase-1,TIMP-1)的表达水平,探讨二者在组织和血浆中表达水平的相关性,评价它们与UC病情严重程度的关系,进而研究血浆中MMP-1、TIMP-1作为诊断UC的新的生物学指标的可行性和有效性,为临床工作提供一定的理论依据。
方法:收集30例经临床表现、肠镜及病理证实为UC患者的结肠粘膜活检组织及外周静脉血,根据病情及病理学诊断分为轻及中-重型(因重型仅3例,故并到中型一起统计)。同时,收集15例正常人的结肠粘膜组织及外周血作为对照。采用逆转录-聚合酶链反应(RT-PCR)及免疫组织化学染色对结肠组织中MMP-1、TIMP-1进行mRNA及蛋白水平的检测,采用酶联免疫检测技术(ELISA法)对血浆中MMP-1、TIMP-1的表达水平进行检测,并对二者在结肠组织与血浆之间表达水平的相关性以及与临床病情之间的关系进行统计学分析。
结果:1、UC患者结肠组织中MMP-1、TIMP-1的表达在mRNA及蛋白水平均较正常对照组明显增加(P<0.05),且MMP-1、TIMP-1的表达水平与病情严重程度呈正相关(P<0.05)。
2、UC患者血浆中MMP-1、TIMP-1的表达水平较对照组明显增高(P<0.05),其中TIMP-1的表达水平与病情严重程度呈正相关,病情越重,其表达量越高(P<0.05);MMP-1的表达只在中-重型的UC患者中增加明显(P<0.05),在轻型中的表达较对照组无统计学意义(P>0.05)。
3、MMP-1在结肠组织与血浆中的表达水平之间有相关性,相关系数为0.805(P<0.05),为非线性相关(P=0.282>0.05);TIMP-1在结肠组织与血浆中的表达水平之间有相关性,相关系数为0.908(P<0.05),为非线性相关(P=0.062>0.05)。
4、在组织与血浆中,MMP-1与TIMP-1表达之间均具有相关性(P<0.05),相关系数分别为0.986、0.914;组织与血浆中TIMP-1与病情之间均具有相关性(P<0.05),相关系数分别为0.822、0.658;而MMP-1及MMP-1/TIMP-1在组织中与病情有相关性(P<0.05),相关系数分别为0.926、0.678,二者在血浆中的表达与病情无相关性(P>0.05),相关系数分别为0.309、0.307。
结论:1、UC患者MMP-1、TIMP-1在结肠组织与血浆中的表达水平之间均呈非线性正相关,血浆中MMP-1和TIMP-1的表达可以分别反映组织中二者的表达水平。
2、结肠组织与血浆中TIMP-1表达与UC患者的病情严重程度呈正相关;MMP-1在结肠组织中的表达与病情严重度呈正相关,而在血浆中的表达水平只与中重型的UC患者的病情严重度呈正相关。
3、血浆中MMP-1和TIMP-1,尤其TIMP-1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 examine the expression of matrix metalloproteinase-1(MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in colonic mucosa and in plasma of patients with ulcerative colitis (UC)at the level of mRNA and protein, to investigate the correlation of MMP-1 and TIMP-1 expressed in colonic mucosa and plasma, to analyze their relationships with the severity of clinical symptoms, and to identify whether or not MMP-1 and TIMP-1 expressed in plasma could be used as new, simple and useful biological parameters in diagnosing UC.
Methods: Colonic mucosa and venous blood samples were collected from thirty patients with UC who were classified into two groups: mild and moderate to severe groups according to the clinical symptoms and pathological histology. Meanwhile, specimens from colonic mucosa and plasma in fifteen normal persons were also collected as controls. RT-PCR and immunohistochemistry were used to examine the expression of MMP-1 and TIMP-1 at the level of mRNA and protein. ELISA assay was used to measure their plasma levels. Statistical analysis was carried out to investigate the correlations of MMP-1 and TIMP-1 between the colonic mucosa and plasma and their relationships with the severity of clinical symptoms of the patients.
Results:1.The expression of MMP-1 and TIMP-1 in the colonic mucosa of patients with UC at the level of mRNA and protein was significantly higher than that in controls, and there is a positive correlation between the expression of MMP-1 and TIMP-1 and the severity of clinical symptoms (P<0.05) .
2. The plasma level of MMP-1 and TIMP-1 was significantly higher than that in controls. Expression of TIMP-1 was correlated well with the severity of clinical symptoms (P<0.05), and expression of MMP-1 in moderate to severe group was significantly higher than that in controls (P<0.05), but no significant difference was found between mild and control groups (P>0.05).
3. There was a significant correlation of MMP-1 between colonic mucosa and plasma (P<0.05), the correlating factor was 0.805, but was not linear correlation (P=0.282);there was also a significant correlation of TIMP-1 between colonic mucosa and plasma (P< 0.05), the correlating factor was 0.908, but was not linear correlation neither (P=0.062).
4. In colonic tissue and plasma, there was significant correlation between the expression of MMP-1 and TIMP-1 , the correlating factors were 0.986 and 0.914, respectively; the colonic and plasma TIMP-1 were both correlated with the severity of clinical symptoms (P < 0.05), their correlating factors were 0.822 and 0.658, respectively; the expression of MMP-1 and MMP-1/TIMP-1 ratio was significantly correlated with the severity of clinical symptoms in the colonic tissue (P < 0.05), the correlating factors were 0.926 and 0.678, respectively, but the plasma MMP-1 and MMP-1/TIMP-1 ratio were not (P>0.05).
Conclusions: 1.A positive, but un-linear correlation of MMP-1 and TIMP-1 expression existed between colonic mucosa and plasma, indicating that plasma MMP-1 and TIMP-1 could reflect their expression in the colonic tissue.
2. The expression of TIMP-1 in colonic mucosa and plasma and of MMP-1 in colonic mucosa was significantly correlated with the severity of clinical symptoms, but the plasma MMP-1 was only significantly increased in moderate to severe group.
3. The plasma MMP-1 and TIMP-1, especially TIMP-1, could be used as new, simple and useful biological parameters in the clinical diagnosis of UC.
方法:收集30例经临床表现、肠镜及病理证实为UC患者的结肠粘膜活检组织及外周静脉血,根据病情及病理学诊断分为轻及中-重型(因重型仅3例,故并到中型一起统计)。同时,收集15例正常人的结肠粘膜组织及外周血作为对照。采用逆转录-聚合酶链反应(RT-PCR)及免疫组织化学染色对结肠组织中MMP-1、TIMP-1进行mRNA及蛋白水平的检测,采用酶联免疫检测技术(ELISA法)对血浆中MMP-1、TIMP-1的表达水平进行检测,并对二者在结肠组织与血浆之间表达水平的相关性以及与临床病情之间的关系进行统计学分析。
结果:1、UC患者结肠组织中MMP-1、TIMP-1的表达在mRNA及蛋白水平均较正常对照组明显增加(P<0.05),且MMP-1、TIMP-1的表达水平与病情严重程度呈正相关(P<0.05)。
2、UC患者血浆中MMP-1、TIMP-1的表达水平较对照组明显增高(P<0.05),其中TIMP-1的表达水平与病情严重程度呈正相关,病情越重,其表达量越高(P<0.05);MMP-1的表达只在中-重型的UC患者中增加明显(P<0.05),在轻型中的表达较对照组无统计学意义(P>0.05)。
3、MMP-1在结肠组织与血浆中的表达水平之间有相关性,相关系数为0.805(P<0.05),为非线性相关(P=0.282>0.05);TIMP-1在结肠组织与血浆中的表达水平之间有相关性,相关系数为0.908(P<0.05),为非线性相关(P=0.062>0.05)。
4、在组织与血浆中,MMP-1与TIMP-1表达之间均具有相关性(P<0.05),相关系数分别为0.986、0.914;组织与血浆中TIMP-1与病情之间均具有相关性(P<0.05),相关系数分别为0.822、0.658;而MMP-1及MMP-1/TIMP-1在组织中与病情有相关性(P<0.05),相关系数分别为0.926、0.678,二者在血浆中的表达与病情无相关性(P>0.05),相关系数分别为0.309、0.307。
结论:1、UC患者MMP-1、TIMP-1在结肠组织与血浆中的表达水平之间均呈非线性正相关,血浆中MMP-1和TIMP-1的表达可以分别反映组织中二者的表达水平。
2、结肠组织与血浆中TIMP-1表达与UC患者的病情严重程度呈正相关;MMP-1在结肠组织中的表达与病情严重度呈正相关,而在血浆中的表达水平只与中重型的UC患者的病情严重度呈正相关。
3、血浆中MMP-1和TIMP-1,尤其TIMP-1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 examine the expression of matrix metalloproteinase-1(MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in colonic mucosa and in plasma of patients with ulcerative colitis (UC)at the level of mRNA and protein, to investigate the correlation of MMP-1 and TIMP-1 expressed in colonic mucosa and plasma, to analyze their relationships with the severity of clinical symptoms, and to identify whether or not MMP-1 and TIMP-1 expressed in plasma could be used as new, simple and useful biological parameters in diagnosing UC.
Methods: Colonic mucosa and venous blood samples were collected from thirty patients with UC who were classified into two groups: mild and moderate to severe groups according to the clinical symptoms and pathological histology. Meanwhile, specimens from colonic mucosa and plasma in fifteen normal persons were also collected as controls. RT-PCR and immunohistochemistry were used to examine the expression of MMP-1 and TIMP-1 at the level of mRNA and protein. ELISA assay was used to measure their plasma levels. Statistical analysis was carried out to investigate the correlations of MMP-1 and TIMP-1 between the colonic mucosa and plasma and their relationships with the severity of clinical symptoms of the patients.
Results:1.The expression of MMP-1 and TIMP-1 in the colonic mucosa of patients with UC at the level of mRNA and protein was significantly higher than that in controls, and there is a positive correlation between the expression of MMP-1 and TIMP-1 and the severity of clinical symptoms (P<0.05) .
2. The plasma level of MMP-1 and TIMP-1 was significantly higher than that in controls. Expression of TIMP-1 was correlated well with the severity of clinical symptoms (P<0.05), and expression of MMP-1 in moderate to severe group was significantly higher than that in controls (P<0.05), but no significant difference was found between mild and control groups (P>0.05).
3. There was a significant correlation of MMP-1 between colonic mucosa and plasma (P<0.05), the correlating factor was 0.805, but was not linear correlation (P=0.282);there was also a significant correlation of TIMP-1 between colonic mucosa and plasma (P< 0.05), the correlating factor was 0.908, but was not linear correlation neither (P=0.062).
4. In colonic tissue and plasma, there was significant correlation between the expression of MMP-1 and TIMP-1 , the correlating factors were 0.986 and 0.914, respectively; the colonic and plasma TIMP-1 were both correlated with the severity of clinical symptoms (P < 0.05), their correlating factors were 0.822 and 0.658, respectively; the expression of MMP-1 and MMP-1/TIMP-1 ratio was significantly correlated with the severity of clinical symptoms in the colonic tissue (P < 0.05), the correlating factors were 0.926 and 0.678, respectively, but the plasma MMP-1 and MMP-1/TIMP-1 ratio were not (P>0.05).
Conclusions: 1.A positive, but un-linear correlation of MMP-1 and TIMP-1 expression existed between colonic mucosa and plasma, indicating that plasma MMP-1 and TIMP-1 could reflect their expression in the colonic tissue.
2. The expression of TIMP-1 in colonic mucosa and plasma and of MMP-1 in colonic mucosa was significantly correlated with the severity of clinical symptoms, but the plasma MMP-1 was only significantly increased in moderate to severe group.
3. The plasma MMP-1 and TIMP-1, especially TIMP-1, could be used as new, simple and useful biological parameters in the clinical diagnosis of UC.
引文
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8. Mrtrisian LM. The matrix-degrading metalloproteinases Bioessays 1992; 14:455-463
9. Disebastiano P, Dimola FF et al. Beneficial effect of Batimastat (BB-94), a matrix metalloproteinase inhibitor, in rat experimental colitis Digestion 2001; 63:234-239
10. Stallmach A, EckerⅡet al. Comparable expression of matrix metallproeinase-1 and-2 in pouchitis and ulcerative colitis Gut 2000; 47 (3):415-422
11. Ralf L, Omar H ,Thomas S et al. Expression of matrix Metalloproteinase-2 and-9 and their inhibitors in periphera blood cells of patients with chronic hepatitis CClin Chem 2000; 46 (2):183-192
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14. Stanley Z, Lysik RM, Zarrabi MH et al. Mr 92,000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer Cancer Research 1993; 53:140-146
15. Shu-Hong Ming, Tie-ying Sun, Wei Xiao et al. Matrix metalloproteinases-2,-9 and tissue inhibitor of metalloproteinase-1 in lung cancer invasion and metastasis CMJ 2005; 118 (1):69-72
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23. Holten-Andersen MN, Jarle Christensen I, J?rgen Nielsen H et al. Total levels of tissue inhibitor of metalloproteinases-1 in plasma yield high diagnostic sensitivity and specificity in patients with colon cancer CCR 2002; 8:156-164
24. Takaki Y, Akira T, Osamu K et al. Intratumoral concentrations of tissueinhibitor of matrix metalloproteinase-1 in patients with gastric carcinoma. Cancer 2001; 91 (9):1739-1744
25. Takaki Y, Mitsunori S, Akira T et al. Tissue inhibitor of matrix metalloproteinase-1 in the plasma of patients with gastric carcinoma Cancer 1999; 6 (10):1929-1935
26. Wiercinka-Drapalo A, Jerzy J, Robert F et al. Plasma matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 as biomarkers of ulcerative colitis activity World J Gastroenterol 2003; 9 (12):2843-2845
27. Baugh MD, Perry MJ, Hollander AP et al. Matrix metalloproteinase levels are elevated in inflammatory bowel disease Gastroenterology 1999; 117:814-822
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30. Henni R, Paavo P, Turpeenniemi-Hujanen T. Tissue inhibitor of matrix metalloproteinase-1 is prognostic in head and neck squamous cell carcinoma:c omparison of the circulating and tissue Immunoreactive Protein Clin Cancer Res 2005;11 (9):3257-3264
31. Henni R, Paavo P, Turpeenniemi-Hujanen T. Tissue and circulating immunoreactive protein for MMP-2 and TIMP-2 in head and neck squamous cell carcinoma tissue immunoreactivity predicts aggressive clinical course Modern Pathology 2006; 19:208-217
32.张建军,刘志明.甲状腺癌患者组织与血清中MMP-9和TIMP-1的表达中国普外基础与临床杂志2007;(4):212-216
2. Von Lampe B, Barthel B, Coupland BE 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
3. Ying-De Wang, Pei-Yun Yan. Expression of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in ulcerative colitis World J Gastroenterol 2006; 12 (37):6050-6053
4. Carlos M, Sebastian V, Anna R et al. Increased activity and expression of matrix metalloproteinase-9 in a rat model of distal colitis Am J Physiol Gastrointest Liver Physiol 2003; 284:116-122
5. McKaig BC, McWilliams D, Watson SA et al. Expression and regulation of tissue inhibitor of metalloproteinase-1 and matrix metalloproteinases by intestinal myofibroblasts in inflammatory bowel disease Am J Pathol 2003; 162 (4):1355-1360
6. Wiercinka-Drapalo A, Jerzy J, Robert F et al. Plasma matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 as biomarkers of ulcerative colitis activity World J Gastroenterol 2003; 9 (12):2843-2845
7. Holten-Andersen MN, Jarle Christensen I, J?rgen Nielsen H et al. Total levels of tissue inhibitor of metalloproteinases-1 in plasma yield high diagnostic sensitivity and specificity in patients with colon cancer Clinical Cancer Research 2002; 8:156–164
8. Mrtrisian LM. The matrix-degrading metalloproteinases Bioessays 1992; 14:455-463
9. Disebastiano P, Dimola FF et al. Beneficial effect of Batimastat (BB-94), a matrix metalloproteinase inhibitor, in rat experimental colitis Digestion 2001; 63:234-239
10. Stallmach A, EckerⅡet al. Comparable expression of matrix metallproeinase-1 and-2 in pouchitis and ulcerative colitis Gut 2000; 47 (3):415-422
11. Ralf L, Omar H ,Thomas S et al. Expression of matrix Metalloproteinase-2 and-9 and their inhibitors in periphera blood cells of patients with chronic hepatitis CClin Chem 2000; 46 (2):183-192
12. McKaig BC, McWilliams D. Expression and regulation of tissue inhibitor of metalloproteinase-1 and matrix metal loproteinases by intestinal myofibroblasts in inflammatory bowel disease Am J Pathol 2003; 20 (7):384-386
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