Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the role of tumor necrosis factor-alpha (TNF alpha) in advanced collagenolysis and degradation of connective tissue components in preterm parturition, the effects of human recombinant TNF alpha (hrTNF alpha) on the production of matrix metalloproteinase 1 (MMP-1)/tissue collagenase, MMP-3/stromelysin, tissue inhibitor of metalloproteinases (TIMP), urokinase type-plasminogen activator (uPa) and prostaglandin (PG) E2 in human chorionic cells were examined in vitro. Human chorionic cells, but not amniotic cells, were found to respond to macrophage-conditioned medium (contains mainly interleukin 1) to produce MMP-1 and MMP-3. This indicated that the chorionic cell is one of the MMP-producing cells of fetal membranes. When confluent chorionic cells were treated with hrTNF alpha, the production of MMP-1 and MMP-3 as well as of uPa and PGE2 was greatly increased in a dose-dependent manner. In contrast, the production of TIMP was suppressed by hrTNF alpha. These results suggested that TNF alpha may participate in destruction of collagen and other connective tissue matrix components of fetal membranes and in promotion of uterine contractility in preterm parturition with intraamniotic infection.
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PMID:Tumor necrosis factor-alpha stimulates the biosynthesis of matrix metalloproteinases and plasminogen activator in cultured human chorionic cells. 131 22

To determine the ability of radiation to modulate mesangial cell expression of various molecules involved in promoting extracellular matrix (ECM) accumulation [fibronectin, plasminogen activator-inhibitor 1 (Pai1), and tissue inhibitor of metalloproteinase-2 (Timp2)] and degradation (Tgfb, plasminogen activators u-PA or t-PA, matrix metalloproteinases Mmp2 and Mmp9), primary cultures of rat mesangial cells (passage number 6-11) were placed in serum-free medium 24 h prior to irradiation with single doses of 0.5-20 Gy (137)Cs gamma rays. After irradiation, cells were maintained in serum-free medium for a further 48 h. Irradiation of quiescent mesangial cells resulted in significant (P < 0.05) time- and dose-dependent increases in Fn and Pai1 mRNA and/or immunoreactive protein. Despite an increase in Tgfb1 mRNA, there was little evidence for an increase in total Tgfb protein. Indeed, active levels remained unaltered after irradiation. Irradiation led to differential changes in MMP expression; active Mmp2 levels increased, while Mmp9 levels appeared unaltered. In addition, secretion of plasminogen activators into the medium was unchanged after irradiation, while secretion of Timp2 increased. We conclude that irradiating mesangial cells leads to altered production of various molecules involved in accumulation and degradation of extracellular matrix.
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PMID:Irradiation of rat mesangial cells alters the expression of gene products associated with the development of renal fibrosis. 1040 25

The significance of plasminogen activators and matrix metalloproteases for clinical outcome, growth and metastatic behavior of head and neck squamous cell carcinoma (SCC) is still controversial. The majority of studies has been based on either immunohistological stainings, which provide only limited quantitative information, or in vitro experiments. We analyzed 44 head and neck SCC and 11 mucosa tissue samples for the expression of gelatinolytic or fibrinolytic proteases by quantitative zymographic analysis and compared lytic activities to clinical and histopathological data. We calculated activation ratios for matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) by separate evaluations of inactive and activated MMP forms. Increased gelatinolytic and fibrinolytic activity was found in head and neck SCC when compared to mucosa. Increased values were caused by MMP-9 and urokinase type plasminogen activator, respectively. No statistically significant correlations of either protease lytic activity or activation ratio could be related to T-stage, metastasis, tissue necrosis or the differentiation stage of tumors. The data recorded are compared with previously published reports.
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PMID:Proteolytic patterns of head and neck squamous cell carcinoma. 1047 28

In most organs, remodelling of tissues after morphogenesis is minimal; however, normal ovarian function depends upon cyclical remodelling of the extracellular matrix (ECM). The ECM has a profound effect on cellular functions and probably plays an important role in the processes of follicular development and atresia, ovulation, and development, maintenance and regression of corpora lutea. Matrix metalloproteinases (MMPs; collagenases, gelatinases, stromelysins and membrane-type MMPs) cleave specific components of the ECM and are inhibited by tissue inhibitors of metalloproteinases (TIMPs). MMPs have been detected at all stages of follicular development and probably modulate follicular expansion or atresia within the ovarian stroma. In addition, increased MMP activity appears to be required for ovulation since follicular rupture occurred in the absence of plasminogen activator activity and inhibitors of MMPs blocked follicular rupture. Development and luteolysis of the corpus luteum are accompanied by extensive remodelling of the ECM. Differentiation and regression of luteal cells are associated with construction and degradation of ECM, respectively. There is increasing evidence that ECM components enhance luteinization; whereas loss of ECM results in luteal cell death. Ovine large luteal cells may be the primary type of cell responsible for controlling the extent of remodelling of luteal ECM since they produce TIMP-1, TIMP-2 and plasminogen activator inhibitor 1. The ratio of active MMPs to TIMPs may be important in maintaining an ECM microenvironment conducive to the differentiation of follicular-derived cells into luteal cells, and maintenance of the phenotype of luteal cells.
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PMID:Regulation of ovarian extracellular matrix remodelling by metalloproteinases and their tissue inhibitors: effects on follicular development, ovulation and luteal function. 1069 69

We established and characterized a new mammary tumor cell line, LM2, derived from M2 mammary adenocarcinoma which spontaneously appeared in a BALB/c female mouse. The LM2 cell line has been maintained in culture for more than 40 passages and grows as poorly differentiated elongated cells. Ultrastructural and immunocytochemistry analysis revealed characteristic features of adenocarcinoma. Cytogenetic studies showed that LM2 cells are fundamentally hypotetraploid. They express metalloproteinases (MMP) and show high levels of plasminogen activator type urokinase (uPA). They were sensitive to nitric oxide (NO)-mediated cytotoxicity when NO derived from an exogenous donor. In vivo, although LM2 cells were able to grow in the lungs, they could not metastasize to the same target organ from s.c. primary tumors. The LM2 mouse mammary adenocarcinoma cell line is a suitable model to examine different aspects of tumor biology, in particular those related to the different pathways involved in the metastatic cascade and in the cytotoxicity mediated by NO.
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PMID:Characterization of a fibroblastoid mammary carcinoma cell line (LM2) originated from a mouse adenocarcinoma. 1107 14

Wound healing is a complex process involving the interactions of many different cell types, matrix components and biological factors, including proteinases and cytokines. This study compared the levels of proteinases (matrix metalloproteinases and plasminogen activators), proteinase inhibitors (tissue inhibitors of metalloproteinases and plasminogen activator inhibitors), inflammatory cytokines and growth factors in acute wound fluid samples collected from the surgical drains of elective breast (n = 24) and colorectal (n = 26) patients on the first postoperative day. Gelatin zymography was used to determine matrix metalloproteinase-2 and -9 levels, quenched fluorescence substrate hydrolysis was applied for total MMP activity and enzyme-linked immunoassays were used to quantitate other factors. Colorectal wound fluid samples showed significantly (p < 0.05) greater levels of the matrix metalloproteinases (MMP-1, 2, 3, and 9), tissue inhibitor of metalloproteinases-1, urokinase plasminogen activator receptor and the inflammatory cytokines (interleukin-1beta, -6, and tumor necrosis factor-alpha); e.g., matrix metalloproteinase-3 colon; median 275 (range 11-2.530) ng/ml; breast; 530-400. However, tissue plasminogen activator and growth factor levels (epidermal growth factor, platelet-derived growth factor, basic fibroblast growth factor, transforming growth factor-beta1) were significantly greater in breast samples; e.g., epidermal growth factor breast 468 (103-1, 444) pg/ml; colon 57(1-573). There was no difference in the levels of urokinase type plasminogen activator, plasminogen activator inhibitor-1 and -2, tissue inhibitor of metalloproteinases -2 or vascular endothelial growth factor. Acute wound fluid from different surgical wounds showed different profiles of proteinases, proteinase inhibitors, and cytokines. This may lead to differences in the rate of tissue remodeling and therefore healing in these two wounds in vivo.
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PMID:Proteinases, their inhibitors, and cytokine profiles in acute wound fluid. 1111 51

Previous studies have shown that matrix vesicles isolated from cultures of costochondral growth zone chondrocytes and treated with 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] can activate recombinant human latent transforming growth factor beta1 (rhTGF-beta1). It is unknown what enzyme or other factor in the extracellular organelles is responsible for the activation. This study tested the hypothesis that enzymes present in matrix vesicles can activate latent TGF-beta1 and that this is regulated by 1alpha,25(OH)2D3. To do this, we examined the ability of matrix vesicle extracts to activate small latent rhTGF-beta1. In addition, enzymes previously determined to be present in matrix vesicles were screened for their ability to activate small latent rhTGF-beta1. Recombinant human matrix metalloproteinase 2 (rhMMP-2; 72 kDa gelatinase), rhMMP-3 (stromelysin 1), purified human plasminogen, and purified urokinase (plasminogen activator) were each tested at varying concentrations. To assess the role of cell maturation, we used a cell culture model in which chondrocytes are derived from two distinct zones of rat costochondral cartilage, the resting zone and the growth zone. Matrix vesicles were isolated from these cultures and then tested. The results showed that extracts of matrix vesicles produced by both growth zone and resting zone chondrocytes were able to activate small latent rhTGF-beta1. The effects were dose and time dependent, with greater activity being found in extracts of matrix vesicles from the growth zone chondrocyte cultures. Only rhMMP-3 was able to activate small latent rhTGF-beta1, indicating that stromelysin-1, but not MMP-2, plasminogen, or urokinase, was involved. As observed in the extracts, the effect of rhMMP-3 was time and dose dependent. When anti-MMP-3 antibody was added to matrix vesicle extracts from both cell types, activation of small latent rhTGF-beta1 was dose-dependently blocked. Neither 1alpha,25(OH)2D3 nor 24R,25(OH)2D3 had a direct effect on activation of small latent rhTGF-beta1 by the extracts. However, when intact matrix vesicles were treated with 1alpha,25(OH)2D3, their ability to activate small latent rhTGF-beta1 was increased. Inhibition of phospholipase A2 with quinacrine blocked the 1alpha,25(OH)2D3-dependent effect. These results suggest that the ability of 1alpha,25(OH)2D3-treated matrix vesicles to activate small latent TGF-beta1 is via action of the secosteroid on the matrix vesicle membrane, not on the enzymes responsible for activating latent TGF-beta1. Because matrix vesicles isolated from growth zone chondrocytes have been shown to contain increased phospholipase A2 activity after treatment with 1alpha,25(OH)2D3, it is likely that this secosteroid promotes loss of membrane integrity through phospholipase A2-dependent formation of lysophospholipids, resulting in the release of MMP-3 into the matrix, where latent TGF-beta1 is stored. Taken together, the results of the current study show that matrix vesicles produced by growth plate chondrocytes contain MMP-3, that this enzyme is at least partially responsible for activation of small latent TGF-beta1 in the matrix, and that 1alpha,25(OH)2D3 regulates MMP release from matrix vesicles.
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PMID:Activation of latent transforming growth factor beta1 by stromelysin 1 in extracts of growth plate chondrocyte-derived matrix vesicles. 1145 Jul 4

The plasma fibrinolytic/proteolytic balance was assessed in 60 stable angina patients who underwent control coronary catheterization and the results were correlated with angiographic findings and control samples (n = 20). The concentrations of t-PA, PAI-1, collagenase (MMP-1), tissue inhibitor of MMP (TIMP-1), plasmin-antiplasmin (PAP) complexes and alpha2-macroglobulin (alpha2-M) were measured in plasma samples. The results showed a significant increase of PAP (p <0.001) and a reduction of alpha2-M (p <0.001) in the group of patients when compared to controls, indicating a degree of fibrinolysis/proteolysis activation. There was no correlation between the different parameters analyzed and the extent of angiographically proven atherosclerosis (one or more stenotic vessels), while the t-PA levels were significantly elevated (p <0.03) in patients with coronary stenosis > or =75% or occlusion. We conclude that there is a disturbance of the plasma fibrinolysis/proteolysis in patients with stable angina not related to the extent of atherosclerosis. The t-PA levels may be a good marker for coronary occlusion in these patients.
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PMID:Fibrinolysis/proteolysis balance in stable angina pectoris in relation to angiographic findings. 1152 15

A fragment of rat thoracic aorta within type I collagen gel was employed as a model of angiogenesis, including the processes of cell migration, proliferation and capillary tube formation. Endogenous angiogenic factors in this model were studied. Expressions of vascular endothelial growth factor (VEGF) and its receptor, and proteolytic enzyme activities (matrix metalloprotease-2; MMP-2 and plasminogen activator; PA) increased during angiogenesis. The angiogenesis was inhibited by VEGF receptor kinase inhibitor and MMP inhibitor, confirming that these endogenous factors played an important role in angiogenesis. Interestingly, these inhibitors induced different capillary morphologies, including differences of cell migration and sprouting. Furthermore, dexamethasone (a down-regulator of MMP and PA) and TNP-470 (an endothelial cell growth inhibitor) induced another capillary morphology. The results suggest that the capillary structure in this model is dramatically influenced by the inhibition of angiogenic signalling and extracellular matrix (ECM) degradation. We also found that a novel angiogenesis inhibitor, the microbial metabolite luminacin, which was recently identified by us (Wakabayashi et al., J. Antiobiot., 53, 591-596 (2000)), induced a different morphology compared with other inhibitors examined, suggesting that it has a unique mechanism of action. Our results indicate that this rat aorta model should be useful for screening novel angiogenesis inhibitors.
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PMID:Characterization of rat aortic fragment within collagen gel as an angiogenesis model; capillary morphology may reflect the action mechanisms of angiogenesis inhibitors. 1199 22

Smooth muscle cell (SMC) rarefaction is involved in the development of several vascular pathologies. We suggest that the plasminogen activation system is a potential extracellular signal that can induce pericellular proteolysis and apoptosis of vascular SMCs. Using primary cultures of arterial SMCs, we show that plasmin generated from plasminogen on the cell surface induces cell retraction and fibronectin fragmentation, leading to detachment and morphological/biochemical changes characteristic of apoptosis (also called anoikis). The generation of cell-bound plasmin mediated by tissue-type plasminogen activator (t-PA), constitutively expressed by VSMCs, requires binding of plasminogen to the cell surface and is inhibited by epsilon-aminocaproic acid (IC50=0.9+/-0.2 mM), a competitor of plasminogen binding to membrane glycoproteins. Conversely, addition of alpha2-antiplasmin, which blocks free plasmin in the cell supernatant, could not fully prevent anoikis. Finally, an MMP inhibitor failed to prevent VSMC anoikis, arguing for a direct involvement of plasmin in this phenomenon. Indeed, similar changes are induced by plasmin directly added to VSMCs or to arterial rings, ex-vivo. We show for the first time that pathological anoikis can be triggered by a process that requires functional assembly of the plasminogen activation system on the surface of VSMCs.
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PMID:Pericellular plasmin induces smooth muscle cell anoikis. 1273 9


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