Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thioglycolate-stimulated mouse peritoneal macrophages secrete a Proteinase which degrades insoluble elastin. There is little elastase activity in cell lysates but the bulk of the enzyme accumulates extracellularly during culture in serum-free medium. The secretion of elastase is sustained for over 12 days in culture and continued secretion of elastase requires protein synthesis. Unstimulated macrophages secrete very little elastase activity but can be triggered to secrete higher levels of this enzyme by phagocytosis and intracellular storage of latex particles. The macrophages elastase is a distinctive proteinase differing from the elastases of pancreas and granulocytes and is distinct from the other secreted proteinases of macrophages, namely, collagenase and plasminogen activator. The macrophages elastase is a serine proteinase and is inhibited by di-isopropyl phosphoro-fluoridate, ovoinhibitor, EDTA, dithiothretiol, and serum. Its activity is little affected by soybean trypsin inhibitor, turkey ovomucoid and chloromethyl ketones derived from tosyl lysine, tosyl phenylalanine, and acetyltetra alanine. Hydrolysis by macrophage elastase of chromogenic ester substrates for pancreatic elastase could not be detected. Elastase secretion by stimulated macrophages exceeds that by primary and established fibroblast cell strains. It is likely that elastase secretion by macrophages plays a major role in the pathogenesis of chronic destructive pulmonary diseases such as emphysema.
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PMID:Elastase secretion by stimulated macrophages. Characterization and regulation. 16 96

Elastase activity directed against lung extracellular matrix is currently believed to be important in the pathogenesis of pulmonary emphysema. Although human alveolar macrophages degrade elastin when in direct contact with this substrate in vitro, studies of free elastase activity in medium conditioned by human alveolar macrophages have yielded variable results. As human alveolar macrophages secrete the tissue inhibitor of metalloproteinases (TIMP), an inhibitor of collagenase and of other connective-tissue-derived mammalian metalloproteinases, we speculated that this inhibitor's effects might extend to macrophage elastase. Using metalloproteinase elastase from the murine macrophagelike cell line P388D1, we observed that human alveolar macrophage conditioned medium inhibits metalloproteinase elastase and that this inhibitory activity could be blocked by specific antibody to TIMP. Alpha 2-macroglobulin, another proteinase inhibitor secreted by alveolar macrophages, also inhibited metalloproteinase elastase, but its inhibitory capacity was not blocked by antibody to TIMP. Because detergents are often included in elastase assays, we examined the effects of sodium dodecyl sulfate (SDS). Buffers containing SDS and SDS-treated elastin were found to exert diverse effects on metalloproteinase elastase, TIMP, and alpha 2-macroglobulin activities, including a marked inhibition of metalloproteinase elastase activity by SDS-containing buffers. These findings suggest that detection of secreted metalloproteinase elastase activity by human alveolar macrophages is complicated by the concomitant release by these cells of inhibitors of metalloproteinases, and that assay conditions can markedly influence the results.
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PMID:Human alveolar macrophages secrete an inhibitor of metalloproteinase elastase. 243 67

We have investigated the ability of neutral and lysosomal enzymes of mouse macrophages to degrade the insoluble extracellular matrices secreted by smooth muscle cells, endothelial cells, and fibroblasts. Matrices produced by smooth muscle cells contained glycoproteins, elastin, and collagens, but matrices of endothelial cells and fibroblasts contained no elastin. Sequential enzyme digestion of residual matrix revealed that plasmin, a product of macrophage plasminogen activation, degraded 50-70% of the glycoprotein in the matrices but did not degrade the elastin or the collagens. Purified macrophage elastase degraded glycoprotein and elastin components but had no effect on the collagens. The rate of elastin degradation by macrophage elastase was decreased in the presence of the glycoproteins. In contrast, human granulocyte elastase effectively degraded the matrix glycoproteins, elastin, and, to a lesser extent, collagens, Mammalian collagenase degraded only collagens. Conditioned medium from resident and inflammatory macrophages, containing mixtures of the secreted proteinases, degraded the glycoprotein and elastin components of the matrices. However, conditioned medium was less effective in degrading matrix than comparable amounts of purified macrophage elastase because > 90% of the elastase in the medium was in a latent form. Inclusion of plasminogen in the assays accelerated degradation. In the presence of plasminogen, glycoproteins were degraded readily by medium from P388D1, pyran copolymer-, thioglycollate-, and periodate-elicited macrophages and, to a lesser extent, by medium from endotoxin-elicited and resident macrophages; medium from P388D1, thioglycollate-, and periodate-elicited macrophages was most effective in elastin degradation, and resident, endotoxin-elicited and pyran copolymer-elicited macrophages degraded almost no elastin. The macrophage cathepsins D and B degraded all the matrix components at an optimum pH of 5.5 and acted with the secreted neutral proteinases to degrade the connective tissue macromolecules to amino acids and oligopeptides. These data indicate that macrophages at inflammatory sites contain and secrete proteolytic enzymes that could degrade the extracellular matrix.
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PMID:Degradation of connective tissue matrices by macrophages. I. Proteolysis of elastin, glycoproteins, and collagen by proteinases isolated from macrophages. 700 Sep 66

Matrix metalloproteinases (MMPs) are a family of proteinases that play a major role in the metabolic degradation of extracellular matrix proteins. In order to examine the expression pattern of different MMP or MMP-inhibitor genes two RNase protection assays (RPAs) were developed that allow the simultaneous and semiquantitative assessment of their respective mRNAs. Probes for the detection of MMPs stromelysin 1, 2 and 3, matrilysin, metalloelastase, gelatinase A and B, collagenase and membrane type MMP (MT1-MMP) were included in the first RPA probe set, while probes for tissue inhibitor of matrix metalloproteinase (TIMP) 1, 2, 3 and alpha 2-macroglobulin (alpha 2-M) were included in the second probe set (inhibitor of matrix metalloproteinase-IMP set). Titration experiments revealed that this method allows the detection of MMP and inhibitor mRNAs present in at least 0.03 microgram of spleen poly(A)+ RNA. Both RPA sets were further evaluated by analyzing the expression of MMP and IMP genes in brain, kidney, spleen and liver in a murine model for endotoxemia after intraperitoneal LPS injection. Control animals showed an organ-specific constitutive expression of one or more MMPs and a high expression of TIMPs. Following LPS injection, an organ-specific upregulation or induction of MMP and TIMP RNA species was found. This change was most pronounced in the spleen, while liver, kidney and brain showed minor or no changes in MMP expression. An IMP upregulation was detected in all organs. These RPA probe sets provide a valuable tool for the simultaneous assessment of MMP and IMP gene expression under physiological and pathological conditions.
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PMID:RNAse protection assays for the simultaneous and semiquantitative analysis of multiple murine matrix metalloproteinase (MMP) and MMP inhibitor mRNAs. 932 62

Programmed expression of matrix metalloproteinases is involved in wound healing in various organs. We have previously demonstrated enhanced expression of collagenase-1, stromelysin-1, matrilysin, and tissue inhibitor of metalloproteinases (TIMP-1) in gastrointestinal ulcerations. To further define the role of matrix-degrading enzymes and their inhibitors in intestinal inflammation and ulcerations, the expression of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (HME, MMP-12), and TIMP-3 mRNAs was studied using in situ hybridization and immunohistochemistry in 38 samples representing ulcerative colitis, Crohn's disease, ischemic colitis, and normal intestine. As controls for normally healing intestinal wounds, 12 postoperative samples of rat experimental jejunal anastomoses were also examined. The colitis types studied did not essentially differ in their MMP expression. We found stromelysin-2 mRNA in laminin-5-positive and Ki-67-negative enterocytes bordering the ulcerations. HME was abundantly expressed by macrophages in the vicinity of shedding mucosal epithelium and beneath the necrotic surface of the ulcers. Collagenase-3 and TIMP-3 were expressed by fibroblast-like cells deeper in the remodeling intestinal wall. Expression for stromelysin-2 and collagenase-3 was observed in granulation tissue, but not the epithelium, of the rat anastomoses. Our results suggest a role for stromelysin-2 in epithelial migration and for metalloelastase in macrophage movement and epithelial cell shedding.
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PMID:Distinct expression profiles of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (MMP-12), and tissue inhibitor of metalloproteinases-3 (TIMP-3) in intestinal ulcerations. 954 61

We have recently demonstrated that the blockade of matrix metalloproteinases by local overexpression of the intrinsic inhibitor tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) reduces intimal hyperplasia. We now report a major change in the elastin content of the intima of rat carotid arteries seeded with TIMP-1-overexpressing smooth muscle cells. To understand the mechanism responsible for elastin accumulation, synthesis and degradation of elastin in TIMP-1 and control cell-seeded rats were measured. There were no differences in elastin mRNA or elastin synthesis, as documented by 14[C]proline incorporation between TIMP-1 and control cell-seeded arteries. In contrast, there was an increase in cross-linked elastin in the TIMP-1 group. In addition, in TIMP-1 and control rats, an elastase activity of approximately 28 kD was detected by elastin zymography and was decreased in TIMP-1 cell-seeded vessels. The 28 kD elastolytic activity was inhibited by exogenously added TIMP-1 and EDTA but not by PMSF, suggesting that it was a metalloelastase. Therefore, we have demonstrated that a shift of the proteolytic balance toward protease inhibition by TIMP-1 overexpression does not change elastin synthesis but rather changes posttranslational processing, resulting in increased elastin accumulation.
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PMID:Metalloproteinase blockade by local overexpression of TIMP-1 increases elastin accumulation in rat carotid artery intima. 959 40

During cutaneous wound healing a number of migratory and remodeling events occur that require the action of matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs). In this study, we analyzed the temporal and spatial expression patterns of these molecules during the healing of murine excisional skin wounds. Our data imply that defined phases of repair rely on distinct repertoires of MMP activity and TIMP counterregulation. Reepithelialization was found to be associated with active production of collagenase, 92-kDa gelatinase, and stromelysins-1 and -2 by distinct subpopulations of keratinocytes at the migrating border. Notably, no TIMP transcripts were expressed in the epidermis, but TIMP-1 expression in the wound colocalized with expression of collagenase, 92-kDa gelatinase, and stromelysin-1, albeit in distinct cells. Concomitant with the formation of an extensive hyperproliferative epithelium, TIMP-1 transcripts accumulated at the mesenchymal/epidermal border of the granulation tissue. During later phases of wound repair, we observed an increase in 72-kDa gelatinase and MT1-MMP expression, whereby the transcripts of these colocalizing MMPs were detected exclusively and at high levels in the granulation tissue. At completion of reepithelialization, the expression levels of the MMPs and TIMP-1 seen in epidermal and dermal compartments declined to near-basal levels, whereas the macrophage-specific metalloelastase (MME) reached maximum expression. In reepithelialized wound tissue, MME transcripts were detected in deep layers of reconstituted dermis and seemed to cluster around vascular structures. Systemic glucocorticoid treatment, which is known to result in impaired wound healing, led to a nearly complete shut-off of MME expression. These observations imply an additional role of macrophage-related proteolysis, independent of its classical roles during earlier, inflammatory phases of cutaneous wound repair.
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PMID:Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) are differentially expressed during excisional skin wound repair. 966 17

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a significant role in regulating angiogenesis, the process of new blood vessel formation. Interstitial collagenase (MMP-1), 72 kDa gelatinase A/type IV collagenase (MMP-2), and 92 kDa gelatinase B/type IV collagenase (MMP-9) dissolve extracellular matrix (ECM) and may initiate and promote angiogenesis. TIMP-1, TIMP-2, TIMP-3, and possibly, TIMP-4 inhibit neovascularization. A new paradigm is emerging that matrilysin (MMP-7), MMP-9, and metalloelastase (MMP-12) may block angiogenesis by converting plasminogen to angiostatin, which is one of the most potent angiogenesis antagonists. MMPs and TIMPs play a complex role in regulating angiogenesis. An understanding of the biochemical and cellular pathways and mechanisms of angiogenesis will provide important information to allow the control of angiogenesis, e.g. the stimulation of angiogenesis for coronary collateral circulation formation; while the inhibition for treating arthritis and cancer.
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PMID:Complex role of matrix metalloproteinases in angiogenesis. 979 30

We determined whether the expression of matrix metalloproteinases (MMP) and tissue inhibitors of MMPs (TIMP) in murine macrophages is regulated by the novel synthetic bacterial lipopeptide JBT 3002. Multilamellar liposomes (MLV) encapsulating JBT 3002 (MLV-JBT 3002) stimulated the production of 72-kDa and 92-kDa (gelatinase A and B) type IV collagenase and inhibited the production of murine metalloelastase (MME) in a dose-dependent manner in murine peritoneal macrophages. MLV-JBT 3002 also induced production of TIMP-1. MLV-JBT 3002 did not induce collagenase production in tumor cells. Priming murine macrophages with interferon-gamma (IFN-gamma) inhibited JBT 3002-stimulated production of both MMP-9 and MMP-2 and further inhibited production of MME by a mechanism involving nitric oxide (NO). This conclusion is based on data showing that IFN-gamma failed to inhibit production of MMP in the presence of L-methyl arginine or in macrophages from inducible nitric oxide synthase knockout mice. These data suggest that JBT 3002 differentially regulates the production of various MMPs and TIMP in macrophages.
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PMID:Differential regulation of type IV collagenases and metalloelastase in murine macrophages by the synthetic bacterial lipopeptide JBT 3002. 1072 54

The capacity of inflammatory cell-derived matrix metalloproteinases (MMPs) to cleave tissue factor pathway inhibitor (TFPI) and alter its activity was investigated. MMP-7 (matrilysin) rapidly cleaved TFPI to a major 35-kDa product. In contrast, MMP-1 (collagenase-1), MMP-9 (gelatinase B), and MMP-12 (macrophage elastase) cleaved TFPI into several fragments including the 35-kDa band. However, rates of cleavage were most rapid for MMP-7 and MMP-9. NH(2)-terminal amino acid sequencing revealed that MMP-12 cleaved TFPI at Lys(20)-Leu(21)(close to Kunitz I domain and producing a 35-kDa band), Arg(83)-Ile(84) (between Kunitz I and II domains), and Ser(174)-Thr(175) (between Kunitz II and III domains). MMP-7 and MMP-9 cleaved TFPI at Lys(20)-Leu(21) with additional COOH-terminal processing. These MMPs did not cleave tissue factor (TF), factor VII, and factor Xa. Proteolytic cleavage by MMP-1, MMP-7, MMP-9, and MMP-12 resulted in considerable loss of TFPI activity. These observations indicate specific cleavage of TFPI by MMPs, which broadens their substrate profile. Co-localization of MMPs, TF, and TFPI in atherosclerotic tissues suggests that release of MMPs from inflammatory cell leukocytes may effect TF-mediated coagulation.
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PMID:Matrix metalloproteinases cleave tissue factor pathway inhibitor. Effects on coagulation. 1085 19


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