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)

Kupffer cells exposed to bacterial lipopolysaccharide in vitro synthesized collagenase and released the major portion of it into the extracellular space while the intracellular level of enzyme was not altered significantly. Cycloheximide prevented the appearance of collagenase in the medium indicating de novo synthesis. Indomethacin, an inhibitor of cyclooxygenase, also blocked collagenase synthesis. In line with this observation. Kupffer cells were found to synthesize substantial amounts of prostaglandin E2 when exposed to lipopolysaccharide; concomitantly, cellular cAMP levels were increased. Indomethacin was shown to abolish the stimulated cAMP formation. Addition to the culture medium of cAMP or dibutyryladenosine 3', 5'-monophosphate as well as of prostaglandin E2 or, to a lesser extent, prostaglandin E1 allowed indomethacin-inhibited cells to resume the production of collagenase. It is proposed that in rat Kupffer cells lipopolysaccharide-elicited collagenase synthesis and excretion is mediated sequentially by stimulated production of prostaglandin E2, enhanced adenylate cyclase activity and increased intracellular cAMP levels.
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PMID:Involvement of prostaglandin E and adenosine 3', 5'-monophosphate in lipopolysaccharide-stimulated collagenase release by rat Kupffer cells. 628 7

Polymorphonuclear leukocytes (PMN) are important in corneal disease because of their role as effector cells in inflammation and ulceration. The favorable effect of citrate on corneal ulceration appears to result from inhibition of the PMN. Citrate does not enter the cells but chelates Ca2+ in the extracellular fluid and may promote a loss of some intracellular Ca2+. Isocitrate is the only tricarboxylic acid cycle intermediate that inhibits PMN, also by Ca2+ chelation. When isobutylcyanoacrylate is polymerized, a substance, probably formaldehyde, inhibitory to PMN, continuously leeches from the plastic. Although acetylcysteine has been reported to inhibit collagenase in vitro it has a direct effect of enhancing the respiratory burst and possibly degranulation of PMN stimulated by opsonized zymosan. Dexamethasone had no effect on PMN stimulation while prednisolone was partially inhibitory at high concentrations. Indomethacin exerts an inhibitory effect on all parameters of PMN stimulation. These studies clarify the site and mechanism of citrate action as well as show the importance of knowing the effect of drugs on the PMN.
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PMID:The effect of citrate and other compounds on PMN incubated in vitro: further studies on the site and mechanism of action of citrate. 657 89

The regulatory effect of endogenously synthesized eicosanoid metabolites on the expression of tissue inhibitor of metalloproteinases (TIMP), interstitial collagenase, and 92-kDa gelatinase by human macrophages was examined. TIMP and metalloproteinase production were stimulated with three agonists that produce distinct patterns of eicosanoid synthesis: lipopolysaccharide (10 micrograms/ml), denatured collagen (10 micrograms/ml), or zymosan (1 mg/ml). Indomethacin (3 micrograms/ml) or MK886 (3 microM), a specific inhibitor of 5-lipoxygenase, was used to examine the role of endogenous metabolites of arachidonic acid. Regardless of the agonist used, TIMP production by macrophages was inhibited 65% by indomethacin, synthesis of interstitial collagenase was reduced 70%, and expression of 92-kDa gelatinase was decreased 40%. In contrast, inhibition of leukotriene synthesis had no effect on metalloproteinase or TIMP production. The agonist-stimulated increase in TIMP and collagenase production was directly correlated to the cumulative prostaglandin E2 level induced by the agonist used. However, if response to an agonist was poor, the exogenous addition of prostaglandin E2 could not increase TIMP or collagenase production more than twofold, indicating an important permissive effect of the agonist on the regulation of each protein's expression. The mechanism of indomethacin inhibition of TIMP and collagenase production was studied by labeling the cells with [35S]-methionine and performing immunoprecipitation using specific antiserum. Indomethacin markedly inhibited the lipopolysaccharide-induced biosynthesis of both TIMP and collagenase. Northern analysis revealed parallel suppression of TIMP and collagenase steady-state mRNA levels by indomethacin, indicating pretranslational control. The regulation of inflammatory-cell TIMP and interstitial collagenase expression by prostaglandin E2 suggests that therapy inhibiting the cellular response to prostaglandins may be useful in cutaneous and systemic disease states involving macrophage-mediated connective-tissue destruction.
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PMID:Agonist-induced expression of tissue inhibitor of metalloproteinases and metalloproteinases by human macrophages is regulated by endogenous prostaglandin E2 synthesis. 779 41

Ovine trophoblast interferon modulates the secretion of a number of proteins by ovine endometrium, but only one of these proteins has so far been identified. We examined the effects of trophoblast interferon on the secretion of matrix metalloproteinase-1, -2 and -3 by cultured ovine endometrial cells and determined whether they are mediated via effects on prostaglandin synthesis. Both ovine trophoblast interferon (30 ng ml-1) and human recombinant interferon alpha (50 U ml-1) inhibited the production of latent matrix metalloproteinase-1 and -3 (P < 0.05), as measured by enzyme assays, but had no effect on the secretion of latent matrix metalloproteinase-2. These inhibitory effects were not overcome by PGE2 or PGF2 alpha (each 10 mumol l-1) either alone or in combination. Indomethacin (12 mumol l-1) similarly inhibited the production of latent matrix metalloproteinase-1 and -3, but production was partially restored by adding the prostaglandins either singly or in combination. PGE2 and PGF2 alpha together had no effect on enzyme production. These data were confirmed by gelatin and casein zymography. Northern analysis showed a 4.5-fold increase in the abundance of specific mRNA for latent matrix metalloproteinase-1 following treatment of cells with phorbol myristate acetate, but a marked decrease following interferon treatment. Thus, ovine trophoblast interferon inhibits the production of the latent forms of matrix metalloproteinase-1 and -3 by ovine endometrial cells, and this is independent of its effect on prostaglandin production.
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PMID:Modulation of production of matrix metalloproteinases from ovine endometrial cells by ovine trophoblast interferon. 779 8

1. Collagenases are thought to play a major role in the pathology of gas gangrene caused by Clostridium histolyticum, because they can destroy the connective tissue barriers. We investigated possible mediators involved in the oedema formation and plasma protein extravasation which follow the injection of a collagenase (EC 3.4.24.3) from Clostridium histolyticum into one hind paw of anaesthetized rats. 2. The magnitude of the oedema following a subplantar injection was dependent on the dose of collagenase (30, 100 and 300 micrograms) injected. It reached its maximum within 30 min and remained unchanged for at least 5 h. Plasma protein extravasation into the paw was most pronounced within 20 min of the injection. Heat-inactivated collagenase was ineffective. 3. The B2 bradykinin (BK) antagonist icatibant (D-Arg-[Hyp3-Thi5-D-Tic7- Oic8] bradykinin, formerly named Hoe-140) reduced oedema formation in a dose-dependent manner with a maximal reduction of around 65% at a dose of 100 nmol kg-1 (s.c.). A significant effect could already be observed at a dose of 10 nmol kg-1. The duration of the effect of icatibant (100 nmol kg-1) was found to be at least 3 h. These results demonstrate the high potency and long duration of action of icatibant. Pretreatment of rats with the bradykinin B1 antagonist, des-Arg9-[Leu8]-BK did not affect collagenase-induced paw oedema. Thus, the observed collagenase-induced effects are mainly mediated by BK through activation of B2 receptors. 4. Pretreatment of adult rats with capsaicin (125 mg kg-1, s.c.) three weeks before the collagenase injection caused a significant attenuation of the paw oedema and of plasma extravasation but was significantly less effective than icatibant (100 nmol kg-1, s.c.). The non-peptide substance P antagonist,CP-96,345 (l0 micromol kg-1, i.v.) significantly reduced collagenase-induced oedema formation to a degree comparable with that seen after capsaicin pretreatment. The inhibition by the substance P antagonist was significantly smaller than that seen after icatibant. The inhibitory effect of icatibant in capsaicin pretreated rats, or of icatibant together with CP-96,345 in untreated rats, was not greater than that oficatibant alone in rats treated with the vehicle for either capsaicin or CP-96,345. CP-96,344(10 micromol kg-1, i.v.), the inactive enantiomer of CP-96,345, did not affect collagenase-induced paw oedema. In capsaicin-pretreated rats, CP-96,345 (10 micromol kg-1, i.v.) did not reduce collagenase-induced paw oedema.The subplantar injection of bradykinin (30 nmol) induced a paw oedema comparable with that induced by collagenase (100 microg). CP-96,345 (10 micromol kg-1, i.v.), but not CP-96,344 (1O micromol kg-1, i.v.),significantly reduced the bradykinin-induced paw oedema. These findings indicate that collagenase leads to the release of bradykinin; bradykinin then stimulates afferent C-fibre terminals and causes the release of substance P and probably also neurokinin A, which augment the oedema-inducing effect of bradykinin.5. Indomethacin or mepyramine plus cimetidine failed to inhibit collagenase-induced paw oedema.Thus, prostaglandins and histamine do not seem to be involved in collagenase-induced paw oedema.6. After subplantar injection of collagenase, the sensitivity scores in a modified formalin-test rapidly increased during the first 10 min. This increase was abolished by pretreatment with icatibant(100 nmol kg-1, s.c.) indicating that the stimulation of nociceptive afferent neurones following injection of collagenase is due to the action of released kinins.7. In conclusion, bradykinin appears to be the main mediator of inflammation induced by a collagenase from Clostridium histolyticum. As well as having direct relevance to a known pathological condition,collagenase-induced paw oedema could prove to be a useful model in inflammation research and in the investigation of bradykinin antagonists. The present results might provide an experimental basis for clinical investigations of the effects of icatibant in infectious diseases where the release of collagenases from bacteria causes rapid spreading of inflammation.
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PMID:Mediation by bradykinin of rat paw oedema induced by collagenase from Clostridium histolyticum. 791 9

In order to establish an experimental system to assess the production of endothelium-derived relaxing factor (EDRF) by cultured human umbilical vascular endothelial cells (HUVECs), the effect of endothelial cells on thrombin-induced platelet aggregation was examined. Cultured HUVECs were harvested from umbilical veins by collagenase treatment. The platelet aggregation experiments were performed using cuvettes lined with HUVECs. The cuvettes were prepared by seeding HUVECs in gelatin-coated cuvettes at a cell density of 2 x 10(5) cells/ml and culturing for 48 hours. Thrombin-induced platelet aggregation was inhibited in the presence of HUVECs. This HUVEC-dependent anti-platelet aggregatory effect was enhanced by the addition of bradykinin, which stimulates the production of EDRF, and thrombin-induced platelet aggregation was completely inhibited. Indomethacin reduced the HUVEC-dependent anti-platelet aggregatory effect. These findings suggest that this simple, new experimental system is useful in assessing the production of EDRF by HUVECs and in examining the effects of various chemicals (or agents) on EDRF production.
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PMID:Assessment of production of endothelium-derived relaxing factor (EDRF) by cultured human vascular endothelial cells based on its anti-aggregatory effect on human platelets. 802 24

Linoleic acid (LA), an omega-6 fatty acid, enhanced the appearance of type IV collagenase activity in culture medium conditioned by the metastatic MDA-MB-435 human breast cancer cell line; this effect was maximal with 0.75 microgram/ml LA. Zymography showed an increase in the gelatinolytic 92 kDa metalloproteinase, a form associated with the metastatic phenotype, during culture in the presence of 0.75 microgram/ml LA. Indomethacin, 20 micrograms/ml, completely suppressed the stimulation of collagenase by LA, suggesting a role for the eicosanoids. The tumor cells expressed mRNA for both the 72 and 92 kDa isoforms of type IV collagenase. Basal levels of the 92 kDa mRNA were much higher; both were up-regulated by LA despite the absence of detectable 72 kDa activity in conditioned medium.
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PMID:Stimulation of type IV collagenase expression by linoleic acid in a metastatic human breast cancer cell line. 812 68

The effects of recombinant human interleukin-1 alpha (IL-1 alpha) and murine epidermal growth factor (EGF) on the release of collagenase were studied in an in vitro model system using periosteal explants from rabbit calvariae. Following an incubation period of 72 h it was shown that IL-1 alpha in combination with EGF (IL-1 alpha + EGF) induced a synergistic increase in the amount of collagenase released by periosteal explants. This increase appeared to be at least 10-fold. Most of the enzyme was present in a latent form since the increase in enzyme activity was only detectable after activation by APMA and the molecular weight as determined in immunoblots corresponded to the latent form of this enzyme. Incubations carried out with IL-1 alpha alone resulted in a 2- to 4-fold increase of total enzyme activity, whereas the amount of collagenase in media of EGF-treated periosteal did not surpass control values. A neutralizing anti-IL-1 alpha antibody completely blocked the enhanced release of collagenase as induced both by IL-1 alpha and by IL-1 alpha + EGF. Indomethacin partially prevented the IL-1 alpha + EGF-induced increase in enzyme release, suggesting the involvement of prostaglandins. The amount of tissue inhibitor of metalloproteinases (TIMP) as determined by ELISA was slightly elevated in culture media obtained from all cytokine-treated explants. Comparable results were obtained by Western blot analysis as well as by a functional bioassay. It is suggested that the concomitant presence of the cytokines IL-1 alpha and EGF may play an important role in collagenase-mediated degradation of collagen.
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PMID:Interleukin-1 alpha and epidermal growth factor synergistically enhance the release of collagenase by periosteal connective tissue in vitro. 824 34

The handling and accumulation of salicylic acid (SA) and indomethacin was examined in freshly isolated proximal tubular (PT) cells of the rat kidney in order to determine whether these cells provide a useful tool for studying accumulation of nonsteroidal anti-inflammatory drugs. A PT cell suspension was prepared by collagenase digestion, followed by filtration and isopycnic centrifugation. SA uptake was concentration-dependent and could be inhibited by probenecid. SA accumulated in the PT cells, and therefore, uptake is probably an active process. In the presence of probenecid, no SA accumulation was observed. Indomethacin uptake increased with time up to 2 min. Thereafter, a sharp decrease occurred, probably caused by inhibition of the oxidative phosphorylation. In the presence of probenecid, uptake was significantly reduced and no longer time-dependent. Indomethacin accumulated in the PT cells by a factor of more than 25. In the presence of probenecid, accumulation was decreased but was still considerable (approximately 10), probably as a result of binding to cellular protein. We conclude that as a result of carrier-mediated transport which is probenecid-sensitive, SA and indomethacin accumulate in the PT cells. The observed accumulation values are in accordance with previously observed values in the isolated perfused rat kidney. Therefore, freshly isolated PT cells appear to be a simple and useful model for studying the accumulation process of drugs like SA and indomethacin.
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PMID:Accumulation of salicylic acid and indomethacin in isolated proximal tubular cells of the rat kidney. 832 4

We examined the interactive effects of heparin and basic fibroblast growth factor (bFGF) on collagen and DNA synthesis in 21-day fetal rat calvariae. In calvariae treated for 24h with heparin (25 micrograms/ml), a significant inhibition of methyl [3H]thymidine (Tdr) incorporation into DNA and [3H]proline labeling of collagenase-digestible protein (CDP) occurred compared to control. Treatment for 24h with bFGF (10(-11) to 10(-9) M) caused a stimulation of Tdr incorporation. With 96h treatment, bFGF (10(-9) M) inhibited CDP labeling by 61%. Basic FGF in combination with heparin overcame the inhibitory effects of heparin on Tdr incorporation. The combination of bFGF plus heparin produced an even greater inhibition of CDP labeling than either effector alone. To assess the role of prostaglandin E2 (PGE2) in moderating the effects of bFGF, calvariae were treated with bFGF in the presence and absence of indomethacin (10(-6) M), an inhibitor of PGE2 production. Indomethacin did not alter the effects of bFGF on Tdr or CDP. We conclude that heparin and bFGF do interact to modulate collagen synthesis in bone via a PGE2-independent mechanism.
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PMID:Interactive effects of basic fibroblast growth factor and heparin on bone in 21-day fetal rat calvariae. 844 8


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