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)

Immunohistochemical staining of endobronchial biopsies has identified increased expression of the 21-amino-acid peptide endothelin (ET) and the inducible form of the enzyme nitric oxide synthase (iNOS) within the airway epithelium in asthma. Elevated concentrations of ET are also recovered in bronchoalveolar lavage fluid from asthma patients. iNOS generates the gas nitric oxide from L-arginine, and elevated levels of NO in exhaled air have been described in asthma. ET is a potent bronchoconstrictor and levels of ET in lavage and resting airflow obstruction are correlated. The effects of ET on bronchomotor tone may be modified by NO as this is a bronchodilator. The relative balance between ET and NOS may thus contribute to resting bronchomotor tone. ET also stimulates fibroblast proliferation, collagen gene expression and through its inhibitory actions on collagenase will promote airway wall collagen deposition and contributes to airway wall thickening which underlies bronchial hyperresponsiveness. The regulation of these epithelial events may thus be important to the control of asthma.
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PMID:Epithelially derived endothelin and nitric oxide in asthma. 754 73

We studied the expression of candidate molecules for tissue injury in vasculitic neuropathies immunohistochemically, using samples obtained by nerve biopsy from seven patients with necrotizing angitis. In the involved vessels of all samples, numerous infiltrating cells were positive for perforin, nitric oxide synthase (m-NOS), cyclooxygenase-2 (COX-2), or matrix metalloproteinase-1 (MMP-1). Cell-mediated cytotoxicity may be involved in the pathogenesis of small vessel injury in vasculitic neuropathies. In the endoneurium following axonal degeneration, scattered and phagocytosing macrophages showed immunostaining for m-NOS and MMP-1, but COX-2 was all but restricted to phagocytosing macrophages. This suggests a role for prostaglandins in nerve damage.
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PMID:Mechanisms of tissue injury in vasculitic neuropathies. 948 78

To investigate the distribution and potential participation of microglia, the resident defense cells of the central nervous system, in the optic nerve head (ONH) in glaucoma, histological paraffin sections of optic nerves from normal and glaucoma patients with mild to advanced nerve damage were studied using double labeling immunohistofluorescence. A monoclonal antibody for HLA-DR, indicating activated microglia, was colocalized with antibodies for functional proteins. In normal ONHs, microglia do not contain TGF-beta2, COX-2, or TNF-alpha and are not positive for PCNA; however, in glaucomatous ONHs, microglia contain abundant TGF-beta2, TNF-alpha, and PCNA. In glaucomatous eyes, a few microglia are usually positive for COX-2. In normal ONHs, there are rarely microglia containing TGF-beta1, NOS-2, TSP, TIMP-2, and CD68, but, in glaucomatous tissue, a few microglia are positive from the prelaminar to the postlaminar regions. MMP-1, MMP-2, MMP-3, and MMP-14 are constitutively present in the perivascular microglia in normal ONHs and appear to be more abundant in glaucomatous tissue. COX-1, TNF-R1, TIMP-1, and c-fms are constitutively present in normal tissues and appear to be increased in microglia in the glaucomatous ONHs. HSP27 is not present in microglia. In glaucomatous ONHs, microglia become activated and phagocytic and produce cytokines, mediators, and enzymes that can alter the extracellular matrix. Our findings suggest that activated microglia may participate in stabilizing the tissue early in the disease process, but, as the severity of the glaucomatous damage increases, the activities of microglia may have detrimental consequences for the pathological course of glaucomatous optic neuropathy.
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PMID:Activated microglia in the human glaucomatous optic nerve head. 1139 7

This experiment was undertaken to determine the role of macrophage-derived nitric oxide (NO) in mediating lipopolysaccharide (LPS)-induced bone resorption by using an in vitro co-culture system and an in vivo model of infectious bone resorption. Our results demonstrated that LPS stimulated the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-a mRNAs and nitrite synthesis in the J774 mouse macrophage cell line but not in the UMR-106 (rat) and MC3T3-E1 (mouse) osteoblast cell lines. Conditioned media (CM) from LPS-stimulated J774 triggered only low to moderate levels of iNOS mRNAs in MC3T3-E1 and a trivial effect in UMR-106. On the other hand, CM induced matrix metalloproteinase-1 (MMP-1) gene expression in both osteoblast cell lines. The NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) did not alter this effect in MC3T3-E1 and UMR-106, whereas TNF-a antibody diminished the CM-induced MMP-1 gene expression in both cell lines. Interestingly, SNAP, a NO donor, although by itself is not a MMP-1 stimulator for UMR-106, augmented the TNF-alpha-stimulated MMP-1 mRNA production in UMR-106. In a J774/UMR-106 co-culture system, LPS stimulated significant MMP-1 gene expression in UMR-106, and this upregulation was abolished by L-NMMA and TNF-alpha antibodies. Immunohistochemical analysis in a rat model of infectious bone resorption (periapical lesion) showed co-distributions of iNOS+ macrophages and MMP-1+ osteoblasts around the osteolytic areas. Administration of L-NMMA markedly reduced the extent of bone loss and the percentage of MMP-1-synthesizing osteoblasts. These data suggest that NO derived from macrophages after LPS stimulation may enhance bone loss by augmenting the cytokine-induced MMP-1 production in osteoblasts.
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PMID:Nitric oxide promotes infectious bone resorption by enhancing cytokine-stimulated interstitial collagenase synthesis in osteoblasts. 1251 Aug 4

Prostaglandin E1 (PGE1) reduces cell death in experimental and clinical liver dysfunction. We have previously shown that PGE1 preadministration protects against NO-dependent cell death induced by D-galactosamine (D-GalN) through a rapid increase of nuclear factor kappaB (NF-kappaB) activity, inducible NO synthase (NOS-2) expression, and NO production. The present study investigates whether PGE1-induced NO was able to abolish NF-kappaB activation, NOS-2 expression, and apoptosis elicited by D-GalN. Rat hepatocytes were isolated following the classical method of collagenase perfusion of liver. PGE1 (1 micromol/L) was administered 2 hours before D-GalN (5 mmol/L) in primary culture rat hepatocytes. PGE1 reduced inhibitor kappaBalpha degradation, NF-kappaB activation, NOS-2 expression, and apoptosis induced by D-GalN. The administration of an inhibitor of NOS-2 abolished the inhibitory effect of PGE1 on NF-kappaB activation and NOS-2 expression in D-GalN-treated hepatocytes. Transfection studies using different plasmids corresponding to the NOS-2 promoter region showed that D-GalN and PGE1 regulate NOS-2 expression through NF-kappaB during the initial stage of hepatocyte treatment. PGE1 was able to reduce the promoter activity induced by D-GalN. In addition, a NO donor reduced NOS-2 promoter activity in transfected hepatocytes. In conclusion, administration of PGE1 to hepatocytes produces low levels of NO, which inhibits its own formation during D-GalN-induced cell death through the attenuation of NF-kappaB-dependent NOS-2 expression. Therefore, a dual role for NO in PGE1-treated D-GalN-induced toxicity in hepatocytes is characterized by a rapid NO release that attenuates the late and proapoptotic NOS-2 expression.
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PMID:PGE1-induced NO reduces apoptosis by D-galactosamine through attenuation of NF-kappaB and NOS-2 expression in rat hepatocytes. 1556 61

Collagen deposition is an important process that occurs during wound healing. We and others have shown that nitric oxide (NO) is important in tendon healing. The mechanisms whereby healing is enhanced are, however, undetermined. The aim of this study was to investigate whether NO could enhance collagen synthesis in cultured human tendon cells via exogenous NO and via an adenovirus containing the gene for inducible nitric oxide synthase (Ad-iNOS). Tendon cells from the torn edge of the tendons of patients undergoing rotator cuff repair surgery were cultured following collagenase digestion, and stimulated with exogenous NO (SNAP), transfected with Ad-iNOS, and treated with the NOS inhibitor, L-NMMA. Total protein and collagen synthesis were evaluated by (3)H-proline and collagenase sensitive (3)H-proline incorporation in human tendon cells. High doses of exogenous NO (SNAP) inhibited collagen synthesis. Lower doses enhanced total protein and collagen synthesis of the tendon cells. Ad-iNOS successfully transfected active iNOS into human tendon cells in vitro and also enhanced total protein and collagen synthesis of the tendon cells. The NOS inhibitor, L-NMMA, inhibited the effects of iNOS on the cells. Our studies show for first time that nitric oxide can enhance collagen synthesis in human tendon cells in vitro. These results may explain, in part, at least, the beneficial effects of NO donors in animal models and during the treatment of tendonopathies in human clinical trials. .
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PMID:Nitric oxide enhances collagen synthesis in cultured human tendon cells. 1643 53

The pre-administration of PGE(1) reduced inducible nitric oxide synthase (NOS-2) expression and cell death induced by d-galactosamine (d-GalN) in cultured rat hepatocytes. The present study evaluated the role of nitric oxide (NO) during PGE(1) treatment in fully established d-GalN-induced cytotoxicity in cultured human hepatocytes. Human hepatocytes were isolated from liver resections by classic collagenase perfusion. PGE(1) (1 microM) was administered at 2 h before d-GalN (40 mM), or 2 or 10 h after d-GalN in cultured hepatocytes. The production of NO was inhibited by N-omega-nitroso-l-arginine methyl ester (l-NAME) (0.5 mM). Various parameters related to oxidative and nitrosative stress, mitochondrial dysfunction, NF-kappaB activation, NOS-2 expression and cell death were evaluated in hepatocytes. NO mediated mitochondrial disturbances, nitrosative stress and cell death in d-GalN-treated hepatocytes. The administration of PGE(1) 10 h after d-GalN enhanced NF-kappaB activation, NOS-2 expression and nitrosative stress. Although PGE(1) administered at 2 h before or 2h after d-GalN reduced apoptosis and necrosis, its administration 10 h after d-GalN had no beneficial effect on cell death. In conclusion, the administration of PGE(1) during advanced d-GalN cytotoxicity induced nitrosative stress and lost its cytoprotective properties in cultured human hepatocytes.
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PMID:The differential effect of PGE(1) on d-galactosamine-induced nitrosative stress and cell death in primary culture of human hepatocytes. 1664 38

Although adherent junctions have been extensively studied, the role of tight junctions in cancer cell invasion is not sufficiently explored. We investigated whether claudin-1, a component of tight junctions, regulated invasion activity in oral squamous cell carcinoma (OSC) cells. The expression of claudin-1, activity of matrix metalloproteinase (MMP)-2, and cleavage of laminin-5 gamma2 chains were assessed by Western blot analysis, immunohistochemistry, and zymography in OSC cell lines (OSC-4 and NOS-2, highly invasive; OSC-7, weakly invasive) and their xenografts in severe combined immunodeficient (SCID) mice. The influence of claudin-1 small interfering RNA (siRNA) on the invasion activity of the cell lines was also investigated. Compared with OSC-7, both OSC-4 and NOS-2 more strongly expressed claudin-1 and possessed high activities of MMP-2 and MMP-9. Tumors formed in the tongues of SCID mice xenografted with OSC-4, NOS-2, and OSC-7 immunohistochemically revealed strong, moderate, and weak expression of laminin-5 gamma2 chains, respectively, and laminin-5 gamma2 chains were secreted in the conditioned medium of the cancer cells in parallel with the in vivo results. Claudin-1 siRNA largely suppressed the invasion of OSC-4 and decreased the activation of MMP-2, the expression of membrane-type MMP-1 (MT1-MMP), and the cleavage of laminin-5 gamma2. In addition, not only antibodies against MT1-MMP and epidermal growth factor receptor (EGFR) but also MMP-2 and EGFR inhibitors strongly suppressed the invasion activity of OSC-4. These results suggest that claudin-1 up-regulates cancer cell invasion activity through activation of MT1-MMP and MMP-2, which results in enhanced cleavage of laminin-5 gamma2 chains.
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PMID:Tight junction protein claudin-1 enhances the invasive activity of oral squamous cell carcinoma cells by promoting cleavage of laminin-5 gamma2 chain via matrix metalloproteinase (MMP)-2 and membrane-type MMP-1. 1670 50

Inflammatory and infectious conditions were simulated in cultures of ras/myc-transformed serum-free mouse embryo (ras/myc SFME) cells, using interferon-gamma (IFN-gamma, 100 units/ml) and lipopolysaccharide (LPS, 0.5 microg/ml) co-treatment for 24 h, to investigate their effects on the expression of inducible nitric oxide synthase (iNOS) mRNA and the production of NO. Aminoguanidine (AG, 1 mM; an NOS inhibitor) along with IFN-gamma and LPS, S-nitroso-N-acetyl-DL-penicillamine (SNAP, 100 microM; an NO donor) and/or (+/-)-N-[(E)-4-Ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexene-1-yl]-3-pyridine carboxamide (NOR4, 100 microM; an NO donor), were also added to analyze the possible association of NO with matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Co-treatment of cells with IFN-gamma and LPS increased iNOS mRNA expression, NO production, MMP-9 mRNA expression, and 105 kDa MMP-9 production. Additional treatment with the NOS inhibitor AG inhibited NO production, but did not down-regulate the expression of MMP-9 mRNA or 105 kDa MMP-9. The NO donors SNAP and NOR4 did not affect the expression of MMP-9 mRNA, 105 kDa MMP-9 or TIMP-1 mRNA. These results suggest that ras/myc SFME cells respond to infectious and inflammatory conditions and can enhance malignancy as cancer cells due to their increased levels of NO and MMP-9 production, but that NO is not directly associated with MMP-9 in these cells.
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PMID:Ras/myc-transformed serum-free mouse embryo cells under simulated inflammatory and infectious conditions increase levels of nitric oxide and matrix metalloproteinase-9 without a direct association between them. 1766 Sep 54

Ras/myc-transformed serum-free mouse embryo (ras/myc SFME) cells were treated with interferon-gamma (IFN-gamma, 100 units/ml) and/or lipopolysaccharide (LPS, 0.5 microg/ml) for 24 h to investigate the effects of these ligands on the expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Aminoguanidine (AG, 1mM; a nitric oxide synthase [NOS] inhibitor) was also added along with IFN-gamma and LPS to analyze a possible association of NO with invasiveness. Treatment of cells with IFN-gamma alone did not alter MMP-9 mRNA expression or pro-MMP-9 production, but LPS alone and IFN-gamma+LPS co-treatment enhanced them significantly. TIMP-1 mRNA expression remained unchanged with or without treatment and the mRNA expression of MMP-9 exceeded that of TIMP-1 in LPS- or IFN-gamma+LPS-treated cells. Co-treatment of cells with IFN-gamma and LPS up-regulated invasiveness and indicated a possible involvement of NO in the enhancement of invasiveness. These results suggest that ras/myc SFME cells respond to inflammatory and infectious conditions and that they may possibly modulate their characteristics as cancer cells due to their increase in MMP-9 expression and invasion activity.
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PMID:Interferon-gamma and lipopolysaccharide stimulation increases matrix metalloproteinase-9 expression and enhances invasion activity in ras/myc-transformed serum-free mouse embryo cells. 1782 27


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