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)

The contribution of toxic oxygen (O2) metabolites to ischemic renal injury is unclear because they have not been added directly to the kidney and few ways exist to effectively measure and assess the effect of these highly reactive products in biological systems. Our goal was to determine the effect of hydrogen peroxide (H2O2) or H2O2-derived products on renal function and to determine whether H2O2-mediated renal injury was reflected by consumption of dimethylthiourea (DMTU) (an exogenous O2 metabolic scavenger), depletion of renal cortical total glutathione (an endogenous O2 metabolite scavenger), and/or adenosine triphosphate (ATP). We found that addition of glucose oxidase (GO) or H2O2 to isolated perfused rat kidneys caused injury that was manifested by decreases in glomerular filtration rate, perfusion flow rate, and sodium reabsorption and that was prevented by addition of catalase (CAT) (but not inactivated CAT) or large doses of DMTU (15 mM), but not urea (15 mM). To further ascertain if the protective effect of DMTU was due to reacting with a scavenging H2O2, we conducted parallel experiments in which we measured the consumption of smaller doses of DMTU (1 mM) in kidneys perfused with GO or H2O2. We found that addition of increasing concentrations of H2O2 decreased DMTU concentration. Renal cortical total glutathione and ATP levels were also decreased by addition of GO or H2O2. In contrast to perfusion with GO or H2O2, perfusion with elastase or collagenase also caused renal injury and decreases in ATP but did not decrease DMTU concentration or tissue total glutathione. We conclude that H2O2 or H2O2-derived products are acutely toxic to the kidney and that decreases in perfusate DMTU concentration and tissue total glutathione, but not tissue ATP, may be useful for specifically assessing the presence and/or toxicity of H2O2 in renal and other biological systems.
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PMID:O2 metabolite-mediated injury in perfused kidneys is reflected by consumption of DMTU and glutathione. 282 29

Human polymorphonuclear neutrophils (PMN), when exposed to soluble or particulate stimuli, can destroy various types of cells. The purpose of the present work was to investigate the toxicity of phorbol myristate acetate (PMA)-stimulated PMN against hepatocytes. Neutrophils were incubated in basal conditions or after stimulation by 100 ng/ml PMA in the presence of rat hepatocytes isolated by collagenase digestion. Cytotoxicity was quantified by the percentage of alanine aminotransferase (ALAT) activity released by hepatocytes in the culture medium. Whereas unstimulated PMN had only minor effects, PMA-stimulated PMN induced, after a 16-hour incubation, a 29.5% ALAT activity release at a PMN/hepatocyte ratio of 20/1. At the same ratio, stimulated PMN induced a 1.5% and a 16.6% ALAT activity release at 1 and 4 hours, respectively. At 1 hour, electron microscopy showed intimate contacts between PMN and hepatocytes; hepatocytes appeared morphologically normal. Hepatocytic lesions were moderate at 4 hours and marked at 16 hours. Neutrophil-induced hepatocyte toxicity could not be explained by the production of reactive oxygen intermediates since: (a) hepatocyte toxicity was not prevented by either superoxide dismutase or by catalase; (b) PMN obtained from a subject with chronic granulomatous disease were as toxic as PMN obtained from a normal subject. By contrast, a proteinase-mediated mechanism could be implicated since: (a) the supernatant of stimulated PMN induced a 45.9% ALAT activity release, after 16 hours of incubation; (b) three neutral proteinase inhibitors (i.e., alpha 1-proteinase inhibitor, phenylmethylsulfonylfluoride, soybean trypsin inhibitor) as well as fetal calf serum decreased this toxic effect by 82, 86, 81 and 70%, respectively. These inhibitors had no or minor protective effect on the toxicity of stimulated PMN coincubated with hepatocytes. This could be explained by the existence of intimate contacts between PMN and hepatocytes impeding the action of antiproteinases. Our results suggest that PMA-stimulated PMN can damage hepatocytes through the release of proteinases and that the existence of close contacts between PMN and hepatocytes might play a major role in this toxic effect.
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PMID:Toxicity of phorbol myristate acetate-stimulated polymorphonuclear neutrophils against rat hepatocytes. Demonstration and mechanism. 284 80

Degradation of intact cartilaginous tissue (bovine nasal cartilage) by oxygen-derived free radicals (ODFR) generated enzymatically by xanthine oxidase and hypoxanthine was studied. The degree of tissue destruction was determined by measuring the indentation under a defined compression force as well as by the loss of uronic acid- and hydroxyproline-containing matrix components. Cartilage slices altered by prior elastase treatment were more susceptible to oxygen radical attack than were intact tissue specimens. Degradation of cartilage matrix by ODFR was strongly inhibited by superoxide dismutase or catalase. Coincubation of latent collagenase from polymorphonuclear leukocytes with the ODFR-generating system led to activation of collagenolytic activity, resulting in marked degradation of the bovine cartilage slices. In further studies, activated polymorphonuclear leukocyte-collagenase was shown to degrade intact human articular cartilage to a degree of mechanical insufficiency. Thus, our assay system serves as an in vitro model of tissue damage, which may be relevant to pathophysiologic states such as rheumatoid arthritis.
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PMID:Oxygen radicals as effectors of cartilage destruction. Direct degradative effect on matrix components and indirect action via activation of latent collagenase from polymorphonuclear leukocytes. 300 65

Polymorphonuclear leukocytes (PMN) accumulating at inflammatory sites have the potential to degrade collagen by releasing the metalloproteinase collagenase (EC 3.4.24.7), which is stored within the specific granules of these cells in a latent, inactive, form. In order to elucidate the activation mechanism the latent enzyme (molecular weight 91,000) was purified from human PMN and incubated with the oxygen radical-generating system of xanthine oxidase (EC 1.1.3.22) and hypoxanthine. This coincubation resulted in the activation of the latent enzyme as assessed by the collagenolytic attack on human and bovine cartilaginous tissue. Two parameters for collagenolysis were used: loss of hydroxyproline-containing fragments, and mechanical measurements reflecting the stability of tissue specimens. Superoxide dismutase (EC 1.15.1.1) as well as catalase (EC 1.11.1.6) were capable of inhibiting the activation of latent PMN collagenase by the oxygen radical-generating system. The results indicate the hydroxyl radical to be the final oxidant responsible for the activation of latent PMN collagenase. Thus a new activation mechanism of latent collagenase is presented in this paper and discussed together with the potential relevance in pathophysiologic states of acute and chronic inflammation.
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PMID:Activation of latent collagenase from polymorphonuclear leukocytes by oxygen radicals. 303 4

Smooth muscle cells were dissociated from normal rabbit aorta by incubating the tissue in Hanks' solution containing elastase, collagenase, and hyaluronidase. The isolated cells contained significant amounts of the following acid hydrolases: N-acetyl-beta-glucosaminidase, N-acetyl-beta-galactosaminidase, beta-galactosidase, beta-glucuronidase, alpha-mannosidase, beta-glucosidase, acid phosphatase, and cathepsins C and D. The cells were disrupted and fractionated by isopycnic centrifugation on sucrose density gradients in the Beaufay automatic zonal rotor. Lysosomes with a modal density of 1.16 were identified by the distribution of these acid hydrolases and by the latency of N-acetyl-beta-glucosaminidase and beta-galactosidase. Other particulate enzymes studied in these sucrose gradients included cytochrome oxidase and monoamine oxidase (mitochondria), 5'-nucleotidase and leucyl-beta-naphthylamidase (plasma membrane), and catalase (? peroxisome). This microanalytical subcellular fractionation technique is applicable to the study of milligram quantities of many other tissues, both normal and pathological.
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PMID:Lysosomes of the arterial wall. I. Isolation and subcellular fractionation of cells from normal rabbit aorta. 434 42

Eosinophils are a common component of the inflammation of the lower respiratory tract that characterizes the interstitial lung disorders. Bronchoalveolar lavage analyses (n = 680) of 251 patients with interstitial lung disease demonstrated that eosinophils represented greater than 5% of the effector cells comprising the alveolitis in 20% of all lavages. In contrast, lavage of normal individuals (n = 117) showed that eosinophils were never greater than 5% of the total effector cells recovered. To evaluate a possible role for eosinophils in mediating some of the cellular and connective tissue matrix derangements of the lung parenchyma found in interstitial disease, eosinophils were evaluated for the presence of proteases capable of cleaving connective tissue proteins found in the lung and for the ability to mediate cytotoxicity to lung parenchymal cells. Evaluation of guinea pig and human eosinophils demonstrated that eosinophil granules contained a collagenase that specifically cleaved human collagen types I and III, the two major connective tissue components of the human lung parenchyma. In contrast, the eosinophil did not contain an elastase or a nonspecific neutral protease. The eosinophil collagenase appeared to be a metalloprotease, as it was inhibited by ethylenediaminetetraacetate but not by phenylmethanesulfonyl-fluoride or alpha 1-antitrypsin. The eosinophil also has the capacity to injure lung parenchymal cells. Without further stimulation, eosinophils purified from peritoneal exudates of guinea pigs demonstrated spontaneous cytotoxicity for human lung fibroblasts (HFL-1), cat lung epithelial cells (AK-D) and rat lung mesothelial cells (I6B). Under identical conditions, the epithelial cells were more sensitive to eosinophil-mediated cytotoxicity than the fibroblasts or mesothelial cells (P less than 0.01), consistent with the clinical observation that in the interstitial disorders, the alveolar epithelial cells are damaged more commonly than fibroblasts or pleural cells. The eosinophil-mediated cytotoxicity could be partially inhibited by the antioxidants catalase and dimethylsulfoxide suggesting that toxic oxygen radicals play a role in mediating the cellular damage. Importantly, eosinophils purified from bronchoalveolar lavage of human interstitial lung disease also demonstrated spontaneous cytotoxicity for lung epithelial cells. These observations demonstrate that eosinophils are frequent participants of the alveolitis of the interstitial lung disorders and suggest that these cells have the potential to damage the parenchymal cells and collagen matrix of the lower respiratory tract.
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PMID:Eosinophil-mediated injury to lung parenchymal cells and interstitial matrix. A possible role for eosinophils in chronic inflammatory disorders of the lower respiratory tract. 633 Jan 75

Hepatocytes of 2-acetylaminofluorene-induced hyperplastic nodules of rats treated with clofibrate were transferred to primary culture after dispersion by a collagenase perfusion technique. After 48-hr treatment with dimethylnitrosamine (DMN), the resistance to the agent of the cells forming rod-shaped peroxisomes was examined. Catalase activity of the DMN-resistant cells was also determined. At concentrations of 10(-3)M and 10(-4)M DMN, the resistant cell population of hepatocytes with rod-shaped peroxisomes was larger than that of the cells without abnormal peroxisomes. On the other hand, the catalase activity of the attached cells that remained after DMN treatment decreased as the concentration of DMN was increased. The cells showing a stronger induction of the enzyme activity were found to be more sensitive to the cytotoxicity of DMN and they became detached from the culture dishes.
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PMID:Primary culture of preneoplastic hepatocytes from rats treated with 2-acetylaminofluorene and clofibrate: relationship between resistance to dimethylnitrosamine and responsiveness of peroxisomes. 711 36

It has been suggested that IL-1 produces cartilage matrix degradation by metalloproteinases such as collagenase and that such degradation is regulated by metalloproteinase inhibitors. In the present study, the effects of IL-6 and oxygen radical scavengers on cartilage matrix degradation were studied. Superoxide dismutase, catalase, or methionine all significantly inhibited cartilage matrix degradation both in IL-1 beta-stimulated and unstimulated experimental conditions. Both 10 mM EDTA and 100 nM tissue inhibitor of metalloproteinase (TIMP) significantly inhibited cartilage matrix degradation. The addition of methionine significantly inhibited collagenase activity produced in the culture supernatants of chondrocytes stimulated with IL-1 beta. IL-6 significantly suppressed cartilage matrix degradation produced spontaneously or by IL-1 beta stimulation in chondrocytes. IL-6 inhibited superoxide production by chondrocytes both in IL-1 beta-stimulated or unstimulated conditions. These results suggest that oxygen radicals are involved in cartilage matrix degradation mediated by both paracrine and autocrine IL-1 mechanisms and that oxygen radical-mediated activation of collagenase in chondrocytes may explain the mechanisms of how oxygen radicals are involved in cartilage matrix degradation. IL-6 inhibited superoxide production in chondrocytes and thus inhibited cartilage matrix degradation.
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PMID:Role of oxygen radicals and IL-6 in IL-1-dependent cartilage matrix degradation. 784 4

Our previous work indicated that energy transduction, as measured by myocyte respiration, was inhibited by hydrogen peroxide, but the mitochondrial membrane potential was relatively unaffected. Therefore, we determined in the present study the critical steps in mitochondrial energy transduction by measuring the sensitivity to hydrogen peroxide of NADH-CoQ reductase, ATP synthase, and adenine nucleotide translocase in situ in myocytes. Adult rat heart cells were isolated using collagenase and incubated in the presence of 0.1-10 mM hydrogen peroxide for 30 min. Activities of NADH-CoQ reductase and oligomycin-sensitive ATP synthase were assayed enzymatically with sonicated myocytes, and adenine nucleotide translocase activities were determined by atractyloside-inhibitable [14C]ADP uptake of myocytes, permeabilized by saponin. The NADH-CoQ reductase and ATP synthase activities were inhibited to 77% and 67% of control, respectively, following an exposure to 10 mM hydrogen peroxide for 30 min. The adenine nucleotide translocase activities were inhibited in a concentration- and time-dependent manner and by 10 mM hydrogen peroxide to 44% of control. The dose-response relationship indicated that the translocase was the most susceptible to hydrogen peroxide among the three enzymes studied. Combined treatment of myocytes with 3-amino-1,2,4-triazole, 1,3-bis(2-chloroethyl)-1-nitrosourea and diethyl maleate (to inactivate catalase, to inhibit glutathione reductase activity, and to deplete glutathione, respectively) enhanced the sensitivity of translocase to hydrogen peroxide, supporting the view that the cellular defense mechanism is a significant factor in determining the toxicity of hydrogen peroxide. The results indicate that hydrogen peroxide can cause dysfunction in mitochondrial energy transduction, principally as the result of inhibition of adenine nucleotide translocase.
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PMID:Effects of hydrogen peroxide on mitochondrial enzyme function studied in situ in rat heart myocytes. 821 72

Reactive oxygen species (ROS) have been shown to be important messenger molecules in the induction of several genes. In human dermal fibroblasts the herbicide paraquat (PQ2+) was used to induce intracellular oxidative stress that was modulated by the inhibition of copper, zinc superoxide dismutase (Cu,ZnSOD), glutathione peroxidase (GSHPx), catalase, and blocking of the Fenton reaction. Interstitial collagenase (MMP-1) mRNA increased time dependently for up to 72 h following paraquat treatment. A correlation with the translation of MMP-1 could, however, only be detected up to 24 h, indicating an uncoupling of transcription and translation. Interleukin-1 alpha and beta mRNA showed two peaks at 6 h and 72 h. The inhibition of catalase by aminotriazol (ATZ), inhibition of GSHPx by buthionine sulfoximine (BSO), and blocking the Fenton reaction by the iron chelator desferrioxamine (DFO) in concert led to an increase in steady-state MMP-1 mRNA levels, possibly dependent on intracellular H2O2 increase. This combined treatment potentiated MMP-1 mRNA induction up to 6.5-fold compared to paraquat treated controls. Furthermore, exogenously added H2O2 caused an increase in MMP-1 mRNA levels. In contrast, inhibition of Cu,ZnSOD by diethyldithiocarbamate (DDC), leading to diminished H2O2 production from O2.-, decreased MMP-1 mRNA induction. Collectively, our data provide evidence that H2O2 is an important intermediate in the downstream signalling pathway finally leading to the induction of increased steady state MMP-1 mRNA levels. The synthesis of MMPs may contribute to connective tissue damage in vivo related to photoaging, inflammatory diseases, and tumor invasion.
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PMID:Hydrogen peroxide (H2O2) increases the steady-state mRNA levels of collagenase/MMP-1 in human dermal fibroblasts. 898 Oct 44


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