1.Matrix metalloproteinases in human gliomas: activation of matrix metalloproteinase-2 (MMP-2) may be correlated with membrane-type-1 matrix metalloproteinase (MT1-MMP) expression.
Jin Heang HUR ; Myung Jin PARK ; In Chul PARK ; Dong Hee YI ; Chang Hun RHEE ; Seok Il HONG ; Seung Hoon LEE
Journal of Korean Medical Science 2000;15(3):309-314
To evaluate possible roles of matrix metalloproteinase (MMP)-1, -2, tissue inhibitor of metalloproteinase (TIMP)-1, -2 and membrane-type-1 matrix metalloproteinase (MT1-MMP) in invasion of human gliomas, expressions of these proteins were investigated in ten cases of human glioma and two meningioma tissues and eight human glioma cell lines. In gelatin zymography, MMP-2 activities of glioblastomas were higher than astrocytomas. The activated form of MMP-2 was seen in five of six cases of glioblastomas, but not in astrocytomas. MMP-9 activity was detected in all cases of malignant astrocytomas but the reactivity of MMP-9 was weaker than that of MMP-2. MT1-MMP mRNA expression in glioblastomas was higher than that in astrocytomas. Five cases of glioblastomas with activated form of MMP-2 had MT1-MMP expressions. In vitro, human glioma cell lines with high expression of MT1-MMP also showed high MMP-2 activity. TIMP-1 transcripts were constitutively present in almost all glioma tissues and cell lines, whereas TIMP-2 mRNA were weak especially in malignant gliomas. Imbalance of TIMP-2/MMP-2 was observed using immunoprecipitation analysis in a glioma cell line. High expression of MMP-2 and MT1-MMP is possibly involved in invasiveness of malignant glioma.
Animal
;
Blotting, Northern/methods
;
Brain/pathology
;
Brain Neoplasms/pathology
;
Brain Neoplasms/enzymology*
;
Enzyme Activation
;
Gelatinase A/metabolism
;
Gelatinase A/genetics*
;
Gelatinase B/metabolism
;
Gene Expression Regulation, Enzymologic*
;
Glioma/pathology
;
Glioma/enzymology*
;
Human
;
Metalloendopeptidases/genetics*
;
Papio
;
Tissue Inhibitor-of Metalloproteinase-2/genetics
;
Tissue-Inhibitor of Metalloproteinase-1/genetics
;
Tumor Cells, Cultured
2.Matrix metalloproteinases in human gliomas: activation of matrix metalloproteinase-2 (MMP-2) may be correlated with membrane-type-1 matrix metalloproteinase (MT1-MMP) expression.
Jin Heang HUR ; Myung Jin PARK ; In Chul PARK ; Dong Hee YI ; Chang Hun RHEE ; Seok Il HONG ; Seung Hoon LEE
Journal of Korean Medical Science 2000;15(3):309-314
To evaluate possible roles of matrix metalloproteinase (MMP)-1, -2, tissue inhibitor of metalloproteinase (TIMP)-1, -2 and membrane-type-1 matrix metalloproteinase (MT1-MMP) in invasion of human gliomas, expressions of these proteins were investigated in ten cases of human glioma and two meningioma tissues and eight human glioma cell lines. In gelatin zymography, MMP-2 activities of glioblastomas were higher than astrocytomas. The activated form of MMP-2 was seen in five of six cases of glioblastomas, but not in astrocytomas. MMP-9 activity was detected in all cases of malignant astrocytomas but the reactivity of MMP-9 was weaker than that of MMP-2. MT1-MMP mRNA expression in glioblastomas was higher than that in astrocytomas. Five cases of glioblastomas with activated form of MMP-2 had MT1-MMP expressions. In vitro, human glioma cell lines with high expression of MT1-MMP also showed high MMP-2 activity. TIMP-1 transcripts were constitutively present in almost all glioma tissues and cell lines, whereas TIMP-2 mRNA were weak especially in malignant gliomas. Imbalance of TIMP-2/MMP-2 was observed using immunoprecipitation analysis in a glioma cell line. High expression of MMP-2 and MT1-MMP is possibly involved in invasiveness of malignant glioma.
Animal
;
Blotting, Northern/methods
;
Brain/pathology
;
Brain Neoplasms/pathology
;
Brain Neoplasms/enzymology*
;
Enzyme Activation
;
Gelatinase A/metabolism
;
Gelatinase A/genetics*
;
Gelatinase B/metabolism
;
Gene Expression Regulation, Enzymologic*
;
Glioma/pathology
;
Glioma/enzymology*
;
Human
;
Metalloendopeptidases/genetics*
;
Papio
;
Tissue Inhibitor-of Metalloproteinase-2/genetics
;
Tissue-Inhibitor of Metalloproteinase-1/genetics
;
Tumor Cells, Cultured
3.Eosinophil Inflammation of Nasal Polyp Tissue: Relationships with Matrix Metalloproteinases, Tissue Inhibitor of Metalloproteinase-1, and Transforming Growth Factor-beta1.
Hae Sim PARK ; Sun Sin KIM ; Hyun Ah KIM ; Yu Jin SUH ; Soo Keol LEE ; Dong Ho NAHM ; Young Mok LEE
Journal of Korean Medical Science 2003;18(1):97-102
Eosinophil and mast cell infiltrations are consistent findings in nasal polyp tissue. Previous studies have shown that matrix metalloproteinases (MMPs) may be involved in eosinophil infiltration in airway mucosa of asthmatic patients, and that transforming growth factor-beta1 (TGF-beta1) induces extracellular matrix deposition in nasal polyp tissue. The aim of this study was to evaluate the role of MMPs and tissue-inhibitor of metalloproteinase-1 (TIMP-1) in association with TGF-beta1, eosinophils and mast cell activation in nasal polyp tissue. Nasal polyp tissues from 20 patients who underwent polypectomies were collected and prepared into tissue homogenate. Eosinophil cationic protein (ECP) and tryptase levels were measured by CAP system (Pharmacia, Sweden). MMP-2, MMP-9, TIMP-1 and TGF-beta1 levels were measured by enzyme-liked immunosorbent assay. MMP-2 was the predominant form of MMPs, followed by MMP-9 and TIMP-1. There were significant correlations between ECP, and MMP-9, MMP-2, TGF-beta1 and tryptase, but not with TIMP-1. Significant correlations were noted between tryptase, and MMP-2, MMP-9, and TGF-beta1, but not with TIMP-1. Close correlations were noted between TGF-beta1, and MMP-9 and MMP-2, but not with TIMP-1. MMP-2, MMP-9, and TGF-beta1 may contribute to eosinophil and mast cell migrations into nasal polyp tissue.
Adult
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Asthma/complications
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Blood Proteins/analysis
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Chemotaxis, Leukocyte
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Eosinophilia/etiology
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Eosinophilia/metabolism*
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Eosinophilia/pathology
;
Eosinophils/physiology
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Female
;
Gelatinase A/analysis
;
Gelatinase A/physiology*
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Gelatinase B/analysis
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Gelatinase B/physiology*
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Human
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Male
;
Mast Cells/physiology
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Middle Aged
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Nasal Polyps/chemistry*
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Nasal Polyps/etiology
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Nasal Polyps/pathology
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Rhinitis/metabolism
;
Rhinitis/pathology
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Ribonucleases*
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Serine Endopeptidases/analysis
;
Tissue-Inhibitor of Metalloproteinase-1/analysis
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Tissue-Inhibitor of Metalloproteinase-1/physiology*
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Transforming Growth Factor beta/analysis
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Transforming Growth Factor beta/physiology*
4.Serologic and histopathologic study of Chlamydia pneumoniae infection in atherosclerosis: a possible pathogenetic mechanism of atherosclerosis induced by Chlamydia pneumoniae.
Young Goo SONG ; Hyuck Moon KWON ; June Myung KIM ; Bum Kee HONG ; Dong Soo KIM ; Ae Jung HUH ; Kyung Hee CHANG ; Hyo Yul KIM ; Tae Soo KANG ; Byung Kwon LEE ; Dong Hoon CHOI ; Yang Soo JANG ; Hyun Seung KIM
Yonsei Medical Journal 2000;41(3):319-327
Chronic infection and inflammation have recently been implicated as important etiologic agents for atherosclerosis in general and, in particular, ischemic heart disease. Several agents have been suggested as possible candidates for the chronic inflammation including cytomegalovirus, Helicobacter pylori and Chlamydia pneumoniae. We hypothesized that a vascular infection with C. pneumoniae may induce a chronic inflammatory reaction in the host vascular tissue and activated inflammatory cells may express inflammatory mediators such as cyclooxygenase-2 (COX-2) and matrix metalloproteinases (MMPs). At first, we evaluated the relationship between C. pneumoniae infection and atherosclerosis indirectly by serologic study, and then, to confirm our hypothesis, we performed an immunohistochemical study of atherosclerotic plaques. The seropositive rate of anti-Chlamydia pneumoniae IgG was higher in the disease group (Group I, 59.8%, n = 254) than in the negative control group (Group III, 47.4%, n = 97) (p = 0.041), but the anti-Chlamydia pneumoniae IgA was not different in seropositivity between the two groups (Group I, 64.6%; Group III, 57.7%). The simultaneous seropositive rates of both IgG and IgA were 56.7% in Group I and 43.3% in Group III (p = 0.033). In subgroups without the conventional risk factors of atherosclerosis, these findings were more prominent. Furthermore, we performed immunohistochemical staining on the atherosclerotic aortic tissues obtained from patients that were seropositive to C. pneumoniae (n = 5), by using antibodies to C. pneumoniae, COX-2, and MMP-9. The immunoreactivity for COX-2 and MMP-9 increased in the atherosclerotic plaques itself, predominantly in the surrounding area of immunoreactive C. pneumoniae. These findings support our hypothesis and C. pneumoniae may participate in a pathogenetic mechanism for atherogenesis or progression of atherosclerosis. The present study may open a promising perspective concerning future therapeutic trials of chronic inflammation related atherogenesis under pathophysiological conditions.
Aged
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Arteriosclerosis/pathology*
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Arteriosclerosis/microbiology*
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Arteriosclerosis/metabolism
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Chlamydia Infections/complications*
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Chlamydophila pneumoniae
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Female
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Gelatinase B/metabolism
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Human
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Isoenzymes/metabolism
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Male
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Middle Age
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Prostaglandin-Endoperoxide Synthase/metabolism
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Serologic Tests*
5.Correlation between expression of matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) and angiogenesis in colorectal adenocarcinoma.
Journal of Korean Medical Science 1999;14(3):263-270
Matrix metalloproteinases-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), which degrade extracellular matrix, are believed to play a crucial role in tumor invasion and metastasis. Angiogenesis is also perceived as an important step in tumor growth and metastasis. To investigate the expression of MMPs and the correlation between the expression of MMPs and angiogenesis in colorectal adenocarcinoma, we studied 72 cases of colorectal adenocarcinoma in Inha University Hospital from 1996 to 1997. We evaluated the expression of MMPs by immunohistochemistry and angiogenesis by counting the microvessels. The expression of MMP-2 was increased according to the Astler-Coller stage (p< 0.05). Angiogenesis in the metastatic group was higher than that of the localized one (p<0.05). The expression of MMP-2 positively correlated with angiogenesis (p<0.05), and marked expression of MMP-9 positively correlated with angiogenesis (p<0.05). The present results suggest that the expression of MMP-2 provides clues for tumor progression and angiogenesis provides significant information to predict whether metastasis is present in colorectal adenocarcinoma.
Adenocarcinoma/pathology
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Adenocarcinoma/metabolism*
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Adenocarcinoma/blood supply
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Adolescence
;
Adult
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Aged
;
Aged, 80 and over
;
Antigens, CD34/biosynthesis
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Collagenases/biosynthesis*
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Colorectal Neoplasms/pathology
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Colorectal Neoplasms/metabolism*
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Colorectal Neoplasms/blood supply
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Gelatinase A
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Gelatinase B
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Gelatinases/biosynthesis*
;
Human
;
Metalloendopeptidases/biosynthesis*
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Middle Age
;
Neovascularization, Pathologic*/pathology
6.Tetraspanin CD9 induces MMP-2 expression by activating p38 MAPK, JNK and c-Jun pathways in human melanoma cells.
In Kee HONG ; Young Myeong KIM ; Doo Il JEOUNG ; Keun Cheol KIM ; Hansoo LEE
Experimental & Molecular Medicine 2005;37(3):230-239
Expression of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), which correlates with tumor invasion and metastasis, has been known to be regulated by several intracellular signaling pathways. Since the CD9 membrane protein has been implicated in signal transduction and malignant progression of cancer cells, we examined the functional involvement of CD9 in the regulation of MMP-2 and MMP-9 expression by using stable CD9 transfectant clones of MelJuso human melanoma cells. The CD9 cDNA-transfected cells with elevated CD9 expression displayed increased MMP-2 and decreased MMP-9 expression when compared with the mock transfectant cells. Among several signal pathway inhibitors tested, SB203580 and SP600125, which inhibit p38 MAPK and JNK respectively, completely blocked the CD9-stimulated MMP-2 expression. Phosphorylation levels of p38 MAPK and c-Jun in MelJuso cells were also significantly increased by CD9 transfection. In addition, the down-regulation of p38 MAPK and JNK by siRNA transfection resulted in a decrease in MMP-2 expression by MelJuso cells. Promoter analysis and gel shift assay showed that the CD9-induced MMP-2 expression is mediated by a functional AP-1 site through interactions with AP-1 transcription factors including c-Jun. These results suggest that CD9 induces MMP-2 expression by activating c- Jun through p38 MAPK and JNK signaling pathways in human melanoma cells.
Antigens, CD/*metabolism
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Electrophoretic Mobility Shift Assay
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Enzyme Activation
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Gelatinase A/genetics/*metabolism
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Gelatinase B/metabolism
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Humans
;
JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/genetics/*metabolism
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Melanoma/*metabolism/pathology
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Membrane Glycoproteins/*metabolism
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Promoter Regions (Genetics)
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Proto-Oncogene Proteins c-jun/*metabolism
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RNA, Small Interfering/pharmacology
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Research Support, Non-U.S. Gov't
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*Signal Transduction
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Skin Neoplasms/metabolism/pathology
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Transcription Factor AP-1/metabolism
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Transfection
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p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/genetics/*metabolism
7.Expression of Epidermal Growth Factor Receptor, ErbB2 and Matrix Metalloproteinase-9 in Hepatolithiasis and Cholangiocarcinoma.
Hyo Jung KIM ; Jae Seon KIM ; Chang Don KANG ; Sung Joon LEE ; Jin Yong KIM ; Jong Eun YEON ; Jong Jae PARK ; Jae Jeong SHIM ; Kwan Soo BYUN ; Young Tae BAK ; Chang Hong LEE
The Korean Journal of Gastroenterology 2005;45(1):52-59
BACKGROUND/AIMS: Hepatolithiasis is a common disease in East Asia and presents as a histological feature of proliferative glands containing mucin. 5-10% of hepatolithiasis is known to be associated with cholangiocarcinoma. Recent studies reported that epidermal growth factor receptor (EGFR) could be activated through heparin binding- EGF cleavage by metalloproteinases. Matrix metalloproteinases (MMPs) which digest the extracellular matrix are required for cancer cell invasion and the expression of MMP-9 is known to be increased in cholangiocarcinoma. However, there has been few studies on the expressions and roles of EGFR and MMP in hepatolithiasis. This study was performed to clarify and compare the expressions of EGFR, erbB2 and MMP-9 in hepatolithiasis and cholangiocarcinoma. METHODS: Surgically resected liver tissues with hepatolithiasis (n=14), cholangiocarcinoma (n=20) and trauma (n=2 as controls) were included. The expressions of EGFR, erbB2 and MMP-9 in tissue samples were examined by immunohistochemistry using respective monoclonal antibodies. RESULTS: In traumatic livers, the expressions of EGFR, erbB2 and MMP-9 were all negative. The expression of EGFR was increased in hepatolithiasis group (79%, 11/14) compared with cholangiocarcinoma group (25%, 5/20) (p<0.05). The expression of erbB2 was detected only in cholangiocarcinoma (25%, 5/20). MMP-9 was increased in both hepatolithiasis (79%, 11/14) and cholangiocarcinoma (95%, 19/20) (p>0.05). CONCLUSIONS: EGFR expression appears to be the dominant component in periductular hyperplasia of hepatolithiasis and MMP-9 is upregulated not only in cholangiocarcinoma but also in hepatolithiasis. This study suggests that EGFR and MMP-9 are associated with cholangiocarcinoma and hepatolithiasis.
Adult
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Bile Duct Neoplasms/*metabolism
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*Bile Ducts, Intrahepatic
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Cholangiocarcinoma/*metabolism
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English Abstract
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Female
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Gelatinase B/*analysis
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Humans
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Lithiasis/*metabolism
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Liver Diseases/*metabolism
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Male
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Middle Aged
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Receptor, Epidermal Growth Factor/*analysis
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Receptor, erbB-2/analysis
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Up-Regulation
8.Lung Matrix Metalloproteinase-9 Correlates with Cigarette Smoking and Obstruction of Airflow.
Min Jong KANG ; Yeon Mok OH ; Jae Cheol LEE ; Dong Gyu KIM ; Myung Jae PARK ; Myung Goo LEE ; In Gyu HYUN ; Sung Koo HAN ; Young Soo SHIM ; Ki Suck JUNG
Journal of Korean Medical Science 2003;18(6):821-827
Cigarette smoking is the most important risk factor for obstruction of airflow in chronic obstructive pulmonary disease (COPD). Matrix metalloproteinases (MMPs) or an imbalance between MMPs and their inhibitors, the tissue inhibitors of MMP (TIMPs), is considered to play a role in the pathogenesis of COPD. We investigated whether the MMPs expression or the imbalance between MMPs and TIMP-1 is associated with the amount of cigarette smoking and the FEV1 value, in the lung parenchyma of 26 subjects (6 non-smokers and 20 cigarette smokers). First, we performed zymographic analysis to identify the profile of the MMPs, which revealed gelatinolytic bands mainly equivalent to MMP-9 in the smokers. We then measured, using enzyme immunoassay, the concentrations of MMP-9 and its inhibitor, TIMP-1. Correlation analysis revealed that both the MMP-9 concentrations and the molar ratios of MMP-9 to TIMP-1 (MMP-9/TIMP-1) were correlated with the amount of cigarette smoking. Furthermore, MMP-9 concentrations were inversely correlated with FEV1. In conclusion, this study shows that MMP-9 expression in human lung parenchyma is associated with cigarette smoking and also with the obstruction of airflow, suggesting that MMP-9 may play a role in the pathogenesis of the cigarette smoke-induced obstruction of airflow known as the characteristic of COPD.
Adult
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Aged
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Female
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Forced Expiratory Volume
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Gelatinase B/*metabolism
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Human
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Lung/*enzymology
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Male
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Middle Aged
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Pulmonary Disease, Chronic Obstructive/*etiology
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*Pulmonary Ventilation
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*Smoking
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Statistics
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Support, Non-U.S. Gov't
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Tissue-Inhibitor of Metalloproteinase-1/metabolism
9.The Changes of Matrix Metalloproteinase-9 Expression in the Gastric Antral Mucosa after Helicobacter pylori Eradication: Immunohistochemical Study.
Heok Soo AHN ; In Hee KIM ; Seung Ok LEE ; Myoung Jae KANG ; Dae Ghon KIM ; Soo Teik LEE
The Korean Journal of Gastroenterology 2004;43(2):90-95
BACKGROUND/AIMS: In this study, we analysed the changes of matrix metalloproteinase-9 (MMP-9) expression in the gastric antral epithelium in respect to H. pylori eradication. METHODS: Twenty patients with H. pylori-positive chronic gastritis or peptic ulcer were studied. The expression of MMP-9 in the gastric antral biopsy specimens were compared before and after H. pylori eradication using immunohistochemical study. The positive rates and intensity of MMP-9 staining were evaluated at surface mucous cells and pyloric gland cells. RESULTS: The positive rate of MMP-9 staining in antral mucosal epithelial cells of H. pylori chronic gastritis is 63.8%. The positive rates of MMP-9 staining in the surface mucous cells and pyloric gland cells were 75.5% and 52.0% before H. pylori eradication, respectively. On the contrary, the rates were 85.5% and 82.0% after eradication. The MMP-9 overexpression in the pyloric gland cells were noticeably increased after H. pylori eradication. Strong positive staining of MMP-9 was increased significantly after H. pylori eradication in the pyloric gland cells. CONCLUSIONS: These results suggest that MMP-9 over-expression is associated with H. pylori infection as a host inflammatory response. The increased expression after H. pylori eradication indicates that MMP-9 may have a important role in remodeling or early tissue repairing process of gastric mucosa.
Adult
;
Aged
;
English Abstract
;
Female
;
Gastric Mucosa/*enzymology
;
Gastritis/drug therapy/enzymology/microbiology
;
Gelatinase B/*metabolism
;
Helicobacter Infections/drug therapy/*enzymology/microbiology
;
*Helicobacter pylori
;
Humans
;
Immunohistochemistry
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Male
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Middle Aged
;
Peptic Ulcer/drug therapy/enzymology/microbiology
;
Pyloric Antrum
10.HCV core protein promotes liver fibrogenesis via up-regulation of CTGF with TGF-beta1.
Ju Yeop SHIN ; Wonhee HUR ; Jin Sang WANG ; Jeong Won JANG ; Chang Wook KIM ; Si Hyun BAE ; Sung Key JANG ; Se Hwan YANG ; Young Chul SUNG ; Oh Joo KWON ; Seung Kew YOON
Experimental & Molecular Medicine 2005;37(2):138-145
Liver cirrhosis is one of the major complications of hepatitis C virus (HCV) infection, but the mechanisms underlying HCV-related fibrogenesis are still not clear. Although the roles of HCV core protein remain poorly understood, it is supposed to play an important role in the regulation of cellular growth and hepatocarcinogenesis. The aim of this study was to examine the role of HCV core protein on the hepatic fibrogenesis. We established an in vitro co-culture system with primary hepatic stellate cell (HSC) isolated from rats, and a stable HepG2-HCV core cell line which had been transfected with HCV core gene. The expressions of fibrosis-related molecules transforming growth factor beta1 (TGF-beta1), transforming growth factor b receptor II (TGF beta RII), alpha-smooth muscle actin (alpha-SMA) and connective tissue growth factor (CTGF) were analyzed via histological or molecular methods. In addition, the expression levels of matrix metaloprotinase-2 (MMP-2) and collagen type I (Col I) from the co-cultured media were measured by zymogram and ELISA, respectively. The expressions of alpha-SMA, TGF-beta1, Col I, TGF beta RII and MMP-2 were significantly increased in the co-culture of stable HepG2-HCV core with HSC. Moreover, the significant increases of CTGF and TGF-beta1 in the HCV core-expressing cells were observed by either Northern or Western blot analysis. These results suggest that HCV core protein may contribute to the hepatic fibrogenesis via up-regulation of CTGF and TGF-beta1.
Actins/metabolism
;
Animals
;
Cell Line, Tumor
;
Cells, Cultured
;
Coculture Techniques
;
Collagen Type I/metabolism
;
Gelatinase A/metabolism
;
Immediate-Early Proteins/*biosynthesis
;
Intercellular Signaling Peptides and Proteins/*biosynthesis
;
Liver/metabolism/*pathology
;
Liver Cirrhosis/*metabolism
;
Male
;
Rats
;
Rats, Sprague-Dawley
;
Receptors, Transforming Growth Factor beta/metabolism
;
Research Support, Non-U.S. Gov't
;
Transforming Growth Factor beta/*metabolism
;
Up-Regulation
;
Viral Core Proteins/genetics/*metabolism