Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinase (MMP)-2 and its hemopexin C domain autolytic fragment (also called PEX) have been proposed to be crucial for angiogenesis. Here, we have investigated the dependency of in vitro angiogenesis on MMP-mediated extracellular proteolysis and integrin alpha(v)beta3-mediated cell adhesion in a three-dimensional collagen I model. The hydroxamate-based synthetic inhibitors BB94, CT1399, and CT1847 inhibited endothelial cell invasion, as did neutralizing anti-membrane-type 1-MMP (MT1-MMP) antibodies and tissue inhibitor of MMP (TIMP)-2 and TIMP-3 but not TIMP-1. This confirmed the pivotal importance of MT1-MMP over other MMPs in this model. Invasion was also inhibited by a nonpeptidic antagonist of integrin alpha(v)beta3, EMD 361276. Although PEX strongly inhibited pro-MMP-2 activation, when contaminating lipopolysaccharide was neutralized, PEX neither affected angiogenesis nor bound integrin alpha(v)beta(3). Moreover, no specific binding of pro-MMP-2 to integrin alpha(v)beta3 was found, whereas only one out of four independently prepared enzymatically active MMP-2 preparations could bind integrin alpha(v)beta3 , and this in a PEX-independent manner. Likewise, integrin alpha(v)beta3 -expressing cells did not bind MMP-2-coated surfaces. Hence, these findings show that endothelial cell invasion of collagen I gels is MT1-MMP and alpha(v)beta3 - dependent but MMP-2 independent and does not support a role for PEX in alpha(v)beta3 integrin binding or in modulating angiogenesis in this system.
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PMID:Dissecting the role of matrix metalloproteinases (MMP) and integrin alpha(v)beta3 in angiogenesis in vitro: absence of hemopexin C domain bioactivity, but membrane-Type 1-MMP and alpha(v)beta3 are critical. 1623 Apr 1

Tranilast is an anti-allergic agent that blocks the release of chemical mediators, such as histamine and leukotrienes from mast cells, and has been reported to suppress keloid and hypertrophic scar formation. Since matrix metalloproteinases (MMPs) play an essential role in tissue remodelling, this study was undertaken to determine whether tranilast suppresses MMP production from neutrophils after lipopolysaccharide (LPS) stimulation in-vitro. Neutrophils from five healthy donors (1 x 10(5) cells/mL) were stimulated with 1.0 microg mL(-1) LPS in the presence or absence of various concentrations of tranilast for 24 h. MMP-7, MMP-8, MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 levels in the culture supernatants were assayed by ELISA. In addition, the influence of tranilast on MMP mRNA expression and transcriptional factor activation in cells cultured for 12 h and 4 h was also evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Tranilast inhibited MMP and TIMP-1 production from neutrophils when cells were treated with the agent at more than 5.0 x 10(-5) M. It also suppressed MMP mRNA expression and transcriptional factor activation induced in neutrophils by LPS stimulation. The results suggest that tranilast inhibits the formation of keloid scarring through the suppression of factors such as MMPs and TIMP, which are essential for tissue remodelling, from inflammatory cells.
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PMID:Effect of tranilast on matrix metalloproteinase production from neutrophils in-vitro. 1639 68

The induction of cytokine synthesis within tumor tissue is a key component of the antivascular action of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in murine tumors. We previously showed that DMXAA alone induced only low amounts of tumor necrosis factor (TNF) in cultured spleen cells, but the addition of suboptimal concentrations of lipopolysaccharide (LPS) provided a costimulatory signal that resulted in 6-10-fold increase in secreted TNF. In this study we investigated the molecular pathway involved, and showed that the addition of NF-kappaB inhibitors salicylate and parthenolide reduced the levels of TNF secreted into the culture supernatants induced with DMXAA (10 microg/ml) alone or in combination with LPS (10 microg/ml). Results from gene arrays, confirmed with RT-PCR, showed that the TNF gene was not upregulated with DMXAA alone, and was only slightly increased above the level of significance when LPS was added simultaneously. This contrasted with secreted TNF protein levels, which increased 5- and 48-fold, respectively, above that in untreated cultures with DMXAA alone or in combination with LPS. In addition to TNF, protein arrays showed IL-6, IL-10, MIP-1alpha, MIP-2, and RANTES were also secreted following treatment with 10 microg/ml DMXAA alone, and IL-4, IFN-gamma, MCP-5, and TIMP-1 were additionally induced using a higher dose of 300 microg/ml DMXAA. The drug is currently showing promise in phase II combination trials, and these studies suggest that DMXAA-induced TNF production in the splenocyte cultures was not due to increased expression of the TNF gene, but through effects on NF-kappaB-dependent posttranscriptional regulation.
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PMID:Inhibition of DMXAA-induced tumor necrosis factor production in murine splenocyte cultures by NF-kappaB inhibitors. 1678 63

An imbalance in the matrix metalloproteinase (MMP) : tissue inhibitor of MMP (TIMP) ratio may be associated with tissue injury. Here, we studied the regulation of TIMP and MMP gene expression in primary glial cultures to ascertain the factors involved in the regulation of these genes in conditions of inflammatory neuropathology. Astrocytes were found to basally express TIMP-1 and TIMP-3 mRNA while microglia expressed only TIMP-2 mRNA. TIMP-4 mRNA was not detectable in either cell type. Treatment with interferon-alpha (IFN-alpha), IFN-gamma, interleukin-3 (IL-3), IL-6 or tumor necrosis factor-alpha (TNF-alpha) did not alter expression of the TIMP genes. However, in astrocytes, but not in microglia, serum, IL-1beta or lipopolysaccharide (LPS) evoked a dose- and time-dependent increase in TIMP-1 mRNA and a coincident down-regulation of the TIMP-3 gene. Astrocytes were found to express mRNA constitutively for MMPs -3, -11 and -14. In contrast, microglia expressed only MMP-12 mRNA under basal conditions. IL-1beta enhanced MMP-3 mRNA levels while LPS increased the MMP-3, -9, -12, -13 and -14 mRNAs. Our findings reveal that regulatory control of TIMP and MMP gene expression by glial cells is agonist- and cell-type specific, and suggest that innate immune signals govern the temporal and spatial expression patterns of TIMP and MMP genes in neuroinflammatory conditions of the CNS.
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PMID:Cell and agonist-specific regulation of genes for matrix metalloproteinases and their tissue inhibitors by primary glial cells. 1689 21

Tobacco smoking is an important risk factor for the development of severe periodontitis. Recently, we showed that nicotine affected mineralized nodule formation, and that nicotine and lipopolysaccharide stimulated the formation of osteoclast-like cells by increasing production of macrophage colony-stimulating factor (M-CSF) and prostaglandin E2 (PGE2) by human osteoblastic Saos-2 cells. In the present study, we examined the effects of nicotine on the expression of matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), the plasminogen activation system including the component of tissue-type plasminogen activator (tPA), urokinase-type PA (uPA), and PA inhibitor type 1 (PAI-1), alpha7 nicotine receptor, and c-fos. We also examined the effect of the nicotine antagonist D-tubocurarine on nicotine-induced expression of MMP-1. Gene expression was examined using real-time polymerase chain reaction (PCR) to estimate mRNA levels. In addition, expression of the MMP, TIMP, uPA, tPA, and PAI-1 proteins was determined by Western blotting analysis. Nicotine treatment caused expression of MMP-1, 2, 3, and 13, but not MMP-14, to increase significantly after 5 or 10 d of culture; MMP-14 expression did not change through day 14. Enhancement of MMP-1 expression by nicotine treatment was eliminated by simultaneous treatment with D-tubocurarine. In the presence of nicotine, expression of uPA, PAI-1, or TIMP-1, 2, 3, or 4 did not change over 14 d of culture, whereas expression of tPA increased significantly by day 7. Nicotine also increased expression of the alpha7 nicotine receptor and c-fos genes. These results suggest that nicotine stimulates bone matrix turnover by increasing production of tPA and MMP-1, 2, 3, and 13, thereby tipping the balance between bone matrix formation and resorption toward the latter process.
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PMID:Nicotine treatment induces expression of matrix metalloproteinases in human osteoblastic Saos-2 cells. 1715 81

This work was undertaken to study the impact of the source of n-3 FA on their incorporation in serum, on blood lipid composition, and on cellular activation. A clinical trial comprising 71 volunteers, divided into five groups, was performed. Three groups were given 400 g smoked salmon (n = 14), cooked salmon (n = 15), or cooked cod (n = 13) per week for 8 wk. A fourth group was given 15 mL/d of cod liver oil (CLO) (n = 15), and a fifth group served as control (n = 14) without supplementation. The serum content of EPA and DHA before and after intervention revealed a higher rise in EPA and DHA in the cooked salmon group (129% rise in EPA and 45% rise in DHA) as compared with CLO (106 and 25%, respectively) despite an intake of EPA and DHA in the CLO group of 3.0 g/d compared with 1.2 g/d in the cooked salmon group. No significant changes were observed in blood lipids, fibrinogen, fibrinolysis, or lipopolysaccharide (LPS)-induced tissue factor (TF) activity, tumor necrosis factor-alpha (TNFalpha), interleukin-8 (IL-8), leukotriene B4 (LTB4), and thromboxane B2 (TxB2) in whole blood. EPA and DHA were negatively correlated with LPS-induced TNFalpha, IL-8, LTB4, TxB2, and TF in whole blood. In conclusion, fish consumption is more effective in increasing serum EPA and DHA than supplementing the diet with fish oil. Since the n-3 FA are predominantly in TAG in fish as well as CLO, it is suggested that the larger uptake from fish than CLO is due to differences in physiochemical structure of the lipids.
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PMID:Enhanced incorporation of n-3 fatty acids from fish compared with fish oils. 1726 56

By studying the responses of nitric oxide in pulmonary fibrosis, the role of inducible nitric oxide synthase in diffuse pulmonary fibrosis as caused by lipopolysaccharide (LPS) treatment was investigated. When compared to rats treated with LPS only, the rats pretreated with 1400W (an iNOS-specific inhibitor) were found to exhibit a reduced level in: (i) NOx (nitrate/nitrite) production, (ii) collagen type I protein expression, (iv) soluble collagen production, and (iv) the loss of body weight and carotid artery PO2. In the pulmonary fibroblast culture, exogenous NO from LPS-stimulated secretion by macrophages or from a NO donor, such as DETA NONOate, was observed to induce the expression of TIMP-1, HSP47, TGF-beta1, and collagen type I as well as the phosphorylation of SMAD-2. After inhalation of NO for 24 h, an up-regulation of collagen type I protein was also noted to occur in rat pulmonary tissue. The results suggest that the NO signal pathway enhanced the expression of TGF-beta1, TIMP-1, and HSP47 in pulmonary fibroblasts, which collectively demonstrate that the NO signal pathway could activate the SMAD-signal cascade, by initiating a rapid increase in TGF-beta1, thereby increasing the expression of TIMP-1 and HSP47 in pulmonary fibroblasts, and play an important role in pulmonary fibrosis.
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PMID:Nitric oxide in the pathogenesis of diffuse pulmonary fibrosis. 1729 83

Monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) are involved in vascular inflammation. We tested the hypothesis, and explored the underlining mechanisms that cilostazol, a phosphodiesterase 3 inhibitor with antiplatelet and antithrombotic properties, inhibits lipopolysaccharide (LPS)-induced MCP-1 and MMP-9 expression. In a rabbit aorta balloon-injury model, administration of LPS increased macrophage infiltration and MCP-1 and MMP-9 expression; cilostazol supplementation prevented this phenomenon and reduced intimal hyperplasia. In contrast, the reverse zymography showed that cilostazol did not affect TIMP-1 expression in serum. In monocytic THP-1 cells, cilostazol and N6,O2'-dibutyryl-cAMP (dioctanoyl-cAMP, a cAMP analog) dose-dependently inhibited LPS-induced MCP-1 protein expression and MMP-9 activation, but did not affect the tissue inhibitor of metalloproteinase-1. Quantitative real-time polymerase chain reaction (PCR) showed that cilostazol inhibited MCP-1 and MMP-9 mRNA expression. Cilostazol significantly inhibited LPS-induced activation of p38, JNK, and nuclear factor-kappaB, and the respective inhibitors of p38 and JNK greatly reduced the level of LPS-induced MCP-1 and MMP-9, suggesting the involvement of the p38 and JNK pathways. In conclusion, cilostazol administered with LPS in vivo reduced neointimal hyperplasia and macrophage infiltration in the balloon-injured rabbit aorta; in vitro, cilostazol inhibits LPS-induced MCP-1 and MMP-9 expression. These data suggest that cilostazol may play an important role in preventing endotoxin- and injured-mediated vascular inflammation.
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PMID:Cilostazol attenuates MCP-1 and MMP-9 expression in vivo in LPS-administrated balloon-injured rabbit aorta and in vitro in LPS-treated monocytic THP-1 cells. 1751 47

Fish oil supplementation has been shown to reduce neutrophil production of inflammatory LTB4 (leukotriene B4) in adults. The present study is the first to examine the effects on neonatal neutrophil function following supplementation in pregnancy. Pregnant women with allergic disease (n=98) were randomized to receive either fish oil [3.7 g of n-3 long-chain PUFAs (polyunsaturated fatty acids)/day] or a placebo supplement for the final 20 weeks of pregnancy. Leukotriene production by neonatal neutrophils was measured after stimulation with the calcium ionophore A23187. This was examined in relation to supplementation, cell membrane fatty acid levels and mononuclear cytokine production. Neutrophil LTB4 production was significantly reduced in neonates whose mothers had received fish oil in pregnancy. This was most evident for isomer 2 of LTB4 (P=0.031), although this was also observed for total LTB4 (P=0.051) and isomer 1 (P=0.088). There was also a trend for lower production of other PUFA metabolites, namely 5-HETE (5-hydroxyeicosatetraenoic acid; P=0.054) in the fish oil group. Accordingly, LTB4 levels were inversely related to membrane n-3 PUFA levels. Less inflammatory products (LTB5) were only produced at very low levels, although there was a trend for higher levels of this metabolite in the fish oil group. Consistent with this, LTB5 levels were positively correlated with n-3 PUFA membrane levels, particularly EPA (eicosapentanoic acid) and negatively correlated with n-6 PUFAs. Neonates with lower neutrophil LTB4 production also had lower production of pro-inflammatory IL (interleukin)-6 responses (r=0.35, P=0.005) and regulatory IL-10 responses (r=0.37, P=0.003) by LPS (lipopolysaccharide)-stimulated neonatal mononuclear cells. In conclusion, maternal dietary changes can modify neonatal neutrophil function. This has implications for the early immune programming, which can be influenced by the inflammatory milieu of local tissues during initial antigen encounter. It also provides evidence of another pathway through which long-chain PUFAs status can influence early immune development.
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PMID:Maternal fish oil supplementation in pregnancy modifies neonatal leukotriene production by cord-blood-derived neutrophils. 1759 21

Asthma is a leading chronic childhood illness in the US. To gain further insight into the pathophysiology of childhood asthma, we studied markers of airway inflammation and possible triggers such as bacterial lipopolysaccharide (LPS) in 18 children with chronic asthma and persistent wheezing who underwent clinically indicated bronchoscopy and bronchoalveolar lavage (BAL). We predominantly found neutrophilic airway inflammation associated with increased levels of IL-8, metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP-1) and MMP-9/TIMP-1 ratio. A significant correlation was found between levels of LPS in BAL and airway neutrophils in BAL from a subgroup of children who had a tendency of increased levels of MMP-9 and TIMP-1, suggesting that increased LPS levels in BAL may contribute to chronic airway inflammation and early remodeling. Our data highlight the importance of defining chronic triggers of early airway inflammation in children and characterizing their inflammation, considering the use of bronchoscopy and BAL. Increased knowledge of airway inflammation in children may help prevent a more severe asthma phenotype and lead to environmental control measures and new treatment strategies to intervene against the establishment of irreversible inflammation.
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PMID:Neutrophilic airway inflammation and association with bacterial lipopolysaccharide in children with asthma and wheezing. 1866 88


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