Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mice deficient in inducible nitric oxide synthase (iNOS; C57Bl/6Ai-[KO]NOS2 N5) or wild-type C57Bl/6 mice were exposed to 1 part/million of ozone 8 h/night or to filtered air for three consecutive nights. Endpoints measured included lavagable total protein, macrophage inflammatory protein (MIP)-2, matrix metalloproteinase (MMP)-9, cell content, and tyrosine nitration of whole lung proteins. Ozone exposure caused acute edema and an inflammatory response in the lungs of wild-type mice, as indicated by significant increases in lavage protein content, MIP-2 and MMP-9 content, and polymorphonuclear leukocytes. The iNOS knockout mice showed significantly greater levels of lung injury by all of these criteria than did the wild-type mice. We conclude that iNOS knockout mice are more susceptible to acute lung damage induced by exposure to ozone than are wild-type C57Bl/6 mice and that protein nitration is associated with the degree of inflammation and not dependent on iNOS-derived nitric oxide.
Am J Physiol Lung Cell Mol Physiol 2002 Mar
PMID:Susceptibility to ozone-induced acute lung injury in iNOS-deficient mice. 1183 50

To elucidate the involvement of type IV collagenases [matrix metalloproteinase (MMP)-2 and MMP-9] and their tissue inhibitors (TIMP-1 and TIMP-2) in the development of gestational trophoblastic disease (GTD), we quantified their levels in hydatidiform mole and choriocarcinoma tissues using specific enzyme-linked immunosorbent assays, and the results were compared with those from normal first trimester placenta. Levels of pro-MMP-2 were increased in hydatidiform mole, and they were further elevated in choriocarcinoma. Levels of pro-MMP-9 in choriocarcinoma and those of TIMP-1 in both hydatidiform mole and choriocarcinoma were also increased. In contrast, TIMP-2 levels were markedly decreased in both hydatidiform mole and choriocarcinoma. Similar results were obtained by the tissue culture of first trimester placenta and hydatidiform mole. Gelatin zymography indicated that the levels of both pro- and activated forms of MMP-2 and MMP-9 were higher in hydatidiform mole and choriocarcinoma. The decreased expression of TIMP-2 in hydatidiform mole and choriocarcinoma was confirmed by Western blot, Northern blot and immunohistochemistry, with the decrease being more pronounced in choriocarcinoma. Taken together, the present study shows that both TIMP-2 mRNA and protein levels are markedly decreased in GTD and the imbalance of MMP-TIMP production, shifted toward greater MMP activity, may be involved in the pathogenesis of GTD.
Mol Hum Reprod 2002 Apr
PMID:Reduced expression of tissue inhibitor of metalloproteinase (TIMP)-2 in gestational trophoblastic diseases. 1191 88

Increased plasma levels of matrix metalloproteinase (MMP)-9 have been shown in cancerous diseases including hepatocellular carcinoma (HCC). Our present aim was to examine whether the measurement of plasma MMP-9 concentration is clinically useful for assessing or monitoring HCC patients. We measured the plasma MMP-9 concentrations in 47 HCC patients, and compared the results with the clinicopathologic features. The plasma MMP-9 levels in patients with HCC were significantly higher than those in the normal controls. The plasma levels of MMP-9 were not related to the size of HCC tumor, the grade of histological differentiation and the serum alpha-fetoprotein level. The plasma levels of MMP-9 were not significantly changed after the effective treatment of HCC tumors. In conclusion, the plasma MMP-9 test was of little value for assessing or monitoring HCC patients.
Res Commun Mol Pathol Pharmacol
PMID:Plasma matrix metalloproteinase-9 (gelatinase B) in patients with hepatocellular carcinoma. 1195 88

Destruction of lung elastin is critical for development of emphysema associated with chronic obstructive pulmonary disease (COPD). Lung macrophages release elastolytic enzymes, including matrix metalloproteinase (MMP)-9, along with tissue inhibitors of MMP (TIMP). We examined the production and activity of macrophage-derived MMP-9 and TIMP-1 from alveolar macrophages (AM) from smokers with COPD, healthy smokers (HS), and nonsmokers (NS). AM were stimulated with either lipopolysaccharide (LPS), interleukin (IL)-1 beta, or cigarette smoke-conditioned culture medium (CSM). AM from patients with COPD released greater amounts of MMP-9 with greater enzymatic activity than HS and NS. In contrast, AM from NS released more TIMP-1 than cells from HS and subjects with COPD. LPS and IL-1 beta caused a dose-dependent increase in MMP-9 release and activity, together with increased levels of TIMP-1. Dexamethasone prevented the increase in MMP-9 release, and increased TIMP-1 release. CSM increased MMP-9 and TIMP-1 release from AM of all groups. Dexamethasone decreased CSM-stimulated MMP-9 release, but had no effect on MMP-9 activity This study suggests that macrophages might be important in the development of COPD because these cells exhibit increased levels of elastolytic activity.
Am J Respir Cell Mol Biol 2002 May
PMID:Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. 1197 Sep 13

Zymography and in situ hybridizition were used to investigate matrix metalloproteinase-2, -9 (MMP-2, -9) activities, and expression of mRNAs for MMP-2, -9 and tissue inhibitors of matrix metalloproteinases (TIMP-1, -2, -3) in the rat uterus during early pregnancy (day 1-7). The zymography results showed two forms of MMP-2 (64 and 67 kDa) in the rat uteri during early pregnancy. The 64-kDa MMP-2 activity was the highest on day 2 (P < 0.01) and higher on day 5 and 6 (P < 0.05). The 67-kDa MMP-2 activity reached the highest on day 5 and 6 (P < 0.01). The 64-kDa MMP-2 activity at the implantation sites was higher than those at interimplantation sites (P < 0.05). Furthermore, the 67 kDa MMP-2 can be converted to 64 kDa forms by incubation with p-aminophenylmercuric acetate (APMA) and trypsin in vitro. The 92-kDa MMP-9 activity was only detected on day 5 and 6 of pregnancy (P < 0.01). In situ hybridization showed that on day 1-4 of pregnancy, both MMP-2 and TIMP-2 mRNAs were evidently localized in the basal stromal cells. On day 5, MMP-2 mRNA signals were decreased in the basal stromal cells and mRNA for TIMP-2 was expressed in the epithelial cells and subepithelial stromal cells. The mRNAs for MMP-9, TIMP-1, and -3 were mainly expressed in epithelial cells on day 1-5. At the implantation site on day 6, the mRNAs for MMP-2, -9, TIMP-1, -2, and -3 were highly expressed in the primary decidual zone surrounding the implanting embryo, and in the whole decidualized stromal cells (the primary and secondary decidual zones) at the implantation site on day 7. The intensities of mRNAs for the TIMPs in decidualized stromal cells at the implantation site on day 6 and 7 were stronger than those for the MMPs. The weak mRNAs for MMP-2, -9, TIMP-1, and -3 but not TIMP-2 were also observed in the ectoplacental cone/trophoblastic cells of the implanting embryos. However, at the interimplantation sites on day 6 and 7, MMP-2, -9, TIMP-1, -2, and -3 mRNAs were weakly expressed in the epithelial cells, subepithelial stromal cells, and myometrium. The results suggested that the implanting rat embryo strongly induced MMP-2 and -9 proteins and gene expression for decidulization and embryo invasion, which were strictly controlled and balanced by the simultaneous expression of TIMP-1, -2 and -3.
Mol Reprod Dev 2002 Jun
PMID:Expression of matrix metalloproteinase -2, -9 and tissue inhibitors of metalloproteinase -1, -2, -3 mRNAs in rat uterus during early pregnancy. 1198 24

The objective of this study was to analyze the correlation between matrix metalloproteinases (MMPs) and angiogenic genes and survival in advanced-stage ovarian carcinomas. Primary and metastatic ovarian carcinomas from patients diagnosed with FIGO stage III-IV disease and followed up to 20 years were studied using mRNA in situ hybridization (ISH). Expression of MMP-2, MMP-9, membrane-type 1-MMP (MT1-MMP), the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and basic fibroblast growth factor (bFGF) was studied. MMP-2, MMP-9 and TIMP-2 mRNA was detected in both tumor and stromal cells, while MT1-MMP was largely confined to tumor cells. In univariate analysis of primary tumors, TIMP-2 and MMP-9 mRNA expression correlated with poor outcome. In metastatic lesions, mRNA expression of TIMP-2, MMP-2, and MT1-MMP correlated with poor survival. In a multivariate analysis of primary tumors, TIMP-2 expression in stromal cells (P=0.006) and MMP-9 expression in tumor cells (P=0.011) retained their predictive value. Intense expression of bFGF mRNA and weak expression of IL-8 mRNA was detected in both stromal and tumor cells in most cases, while VEGF mRNA expression was limited to a few cases. Angiogenic mRNA expression showed no correlation with disease outcome in survival analysis (P>0.05). We conclude that bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. MMP-2, MMP-9, MT1-MMP and TIMP-2 are valid markers of poor survival in advanced-stage ovarian carcinoma.
Mol Cell Endocrinol 2002 Feb 22
PMID:The prognostic value of metalloproteinases and angiogenic factors in ovarian carcinoma. 1198 10

Matrix metalloproteases (MMPs) and tissue inhibitors of metalloproteases (TIMPs) are involved in many cell migration phenomena and produced by many cell types, including neurons and glia. To assess their possible roles in brain injury and regeneration, we investigate their production by glial cells, after brain injury and in tissue culture, and we investigate whether they are capable of digesting known axon-inhibitory proteoglycans. To determine the action of MMPs, we incubated astrocyte conditioned medium with activated MMPs, then did western blots for several chondroitin sulphate proteoglycans. MMP-3 digested all five proteoglycans tested, whereas MMP-2 digested only two and MMP-9 none. To determine whether MMPs or TIMPs are produced by astrocytes in vitro, we tested both primary cultures and astrocyte cell lines by western blotting, and compared them with Schwann cells. All cultures produced at least some MMPs and TIMPs, with no obvious correlation with the ability of axons to grow on those cells. Both MMP-9 and TIMP-3 were regulated by various cytokines. To determine which cells produce MMPs and TIMPs after brain injury, we made lesions of adult rat cortex, and did immunohistochemistry. MMP-2 was seen to be induced in activated astrocytes through the whole thickness of the cortex but not deeper, but MMP-3 was not seen in the injured brain. TIMP-2 and TIMP-3 immunoreactivities were induced in activated astrocytes in deep cortex and the underlying white matter. In situ hybridisation confirmed induction of TIMP-2 in glia as well as neurons, but showed no expression of TIMP-4. These results show that both MMPs and TIMPs are produced by some astrocytes, but TIMP production is particularly strong, especially in deep cortex and white matter which is more inhibitory for axon regeneration. Conversely the MMPs produced may not be adequate to promote migration of cells and axons within the glial scar.
Brain Res Mol Brain Res 2002 Apr 30
PMID:Matrix metalloproteases and their inhibitors are produced by overlapping populations of activated astrocytes. 1200 26

Protease-activated receptor-2 (PAR2) acts as a receptor for trypsin and trypsin-like enzymes. The role of this receptor in airway inflammation is uncertain. In this study we assessed the effect of activation of PAR2 following intranasal administration of the peptide activator of PAR2, SLIGRL, over 72 h in mice. The extent of immune cell infiltration into the airways and activities of matrix metalloprotease-2 (MMP-2) and MMP-9 were assessed in bronchoalveolar lavage (BAL) by differential cell counts and gelatin zymography, respectively. SLIGRL did not cause a change in the number or types of cells retrieved in BAL at any time point and did not alter the levels of MMP-2 and MMP-9 present in BAL. In contrast, similar intranasal administration of bacterial lipopolysaccharide (LPS) caused a large influx of neutrophilic polymorphonuclear leukocytes, which was associated with increased MMP-2 at 3 h only and MMP-9 activity from 3-72 h. Simultaneous administration of SLIGRL and LPS transiently potentiated increased MMP-9 activity at 3 h but markedly inhibited neutrophil influx and elevated MMP-2 activity at 3 h. These findings suggest that PAR2 agonists may be useful therapeutic molecules in pulmonary inflammatory diseases.
Am J Respir Cell Mol Biol 2002 Jun
PMID:Protease-activated receptor-2 activating peptide SLIGRL inhibits bacterial lipopolysaccharide-induced recruitment of polymorphonuclear leukocytes into the airways of mice. 1203 66

Although both hepatocyte growth factor (HGF) and interleukin (IL)-6 play important roles in invasion of cancer cells, interaction between these two critical factors has not been well elucidated. In the present study we demonstrated a two-way interaction between HGF and IL-6 in in vitro invasion of a lung cancer cell line. A549 lung adenocarcinoma cells were stimulated with IL-6, and this treatment induced an upregulation of c-Met/HGF receptor mRNA expression in the cells. In addition, IL-6 enhanced the HGF-induced in vitro cell invasion. This effect was abolished by pretreatment of the cells with either anti-IL-6 neutralizing antibody or with anti-c-Met/HGF receptor blocking antibody. We also found that HGF upregulated the expression of IL-6 receptor mRNA in the same cell line, and that this upregulation enhanced the IL-6-induced cell invasion. Finally, costimulation with HGF and IL-6 showed an additive effect on invasion, and this effect was mediated by production of matrix metalloproteinase (MMP)-2 and MMP-9. These results suggest that HGF and IL-6 upregulate each other's receptors, and thus would cooperatively enhance tissue invasion. They also suggest an "autocrine circuit" among cytokines and growth factors in certain cancer cells which functions to accelerate their biologic activities such as metastatic property.
Am J Respir Cell Mol Biol 2002 Aug
PMID:A two-way interaction between hepatocyte growth factor and interleukin-6 in tissue invasion of lung cancer cell line. 1215 14

Among the many biological characteristics of cancer, matrix-metalloproteinases (MMPs) are essential for tumor invasion and metastasis. To test the possibility of ex vivo model as a therapeutic guideline for MMP inhibitor (MMPI) treatment, we evaluated IC50 of the gabexate mesylate against MMP-9. Thirty-four paired normal and gastric cancer tissues were tested to measure the IC50 of the gabexate mesylate. MMP-9 activity was measured by zymography. Both MMP-9 expression (p=0.04) and IC50 (p=0.02) were higher in cancer than normal tissues. IC50 of the cancer tissues was higher than paired normal tissues especially in cases with large tumor (> or =5 cm) (p=0.03), higher T-stage (p=0.04), lymph node metastasis (p=0.04) and advanced stage (p=0.04). In cancers extending beyond submucosa or in diffuse/mixed type, a tendency of higher IC50 was observed than tumors confined to submucosa or intestinal type cancer despite similar MMP-9 activity between the groups. Patients with high IC50 showed poorer prognosis than patients with low IC50 in curatively-resected group. In multivariate analysis, high IC50 was suggested as an independent prognostic factor. We were able to differentiate the high risk patients using IC50 of gabexate mesylate in ex vivo model. This model can be applied in detecting patients with poor prognosis and patients who may benefit from MMPI treatment.
Int J Mol Med 2002 Sep
PMID:Biological phenotype determination with ex vivo model in gastric cancer for matrix-metalloproteinase inhibitor treatment. 1216 96


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