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)

Vascular endothelial growth factor (VEGF) plays multifunctional roles in vascular permeability, repair and remodelling processes, in addition to the maintenance of vascular structure and function. In the present study, the potential of airway epithelial cell lines, BEAS-2B cells and A549 cells, to release and express VEGF in unstimulated and stimulated conditions was evaluated. The secretion and expression of VEGF were evaluated by enzyme-linked immunosorbant assay and by reverse transcriptase-polymerase chain reaction. The isoforms of released VEGF were determined by high-performance liquid chromatography. BEAS-2B cells and A549 cells released VEGF constitutively. Interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha augmented the release of VEGF in a time- and dose-dependent manner. The released VEGF was 165 amino acid residues in either condition. Pseudomonas aeruginosa lipopolysaccharide (LPS), interferon (IFN)-gamma, smoke extract (SE), neutrophil elastase (NE), and bradykinin stimulated the release of VEGF. Keracinocyte growth factor (KGF), which reduces vascular permeability, also stimulated both cells to release VEGF. VEGF messenger ribonucleic acid (mRNA) was expressed both time- and dose-dependently at 2 h, and declined after 2 h in response to IL-1beta and TNF-alpha. The expression of VEGF mRNA in airway epithelial cells was also augmented by LPS, IFN-gamma, SE, NE, and KGF stimulation. These data suggest that airway epithelial cells may regulate the maintenance of vascular structure and function, as well as vascular permeability, repair and remodelling processes, in a variety of lung conditions by expressing vascular endothelial growth factor.
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PMID:Vascular endothelial growth factor mRNA and protein expression in airway epithelial cell lines in vitro. 1250 3

Secretory leukoprotease inhibitor (SLPI) protects tissue against the destructive action of neutrophil elastase at the site of inflammation. Recent studies on new functions of SLPI have demonstrated that SLPI may play a larger role in innate immunity than merely as a protease inhibitor. To clarify the functions of SLPI in bacterial infections, we generated SLPI-deficient mice (SLPI(-/-) mice) and analyzed their response to experimental endotoxin shock induced by lipopolysaccharide (LPS). SLPI(-/-) mice showed a higher mortality from endotoxin shock than did wild type mice. This may be explained in part by our observation that SLPI(-/-) macro-phages show higher interleukin 6 and high-mobility group (HMG)-1 production and nuclear factor kappaB activities after LPS treatment than do SLPI(+/+) macrophages. SLPI also affects B cell function. SLPI(-/-) B cells show more proliferation and IgM production after LPS treatment than SLPI(+/+) B cells. Our results suggest that SLPI attenuates excessive inflammatory responses and thus assures balanced functioning of innate immunity.
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PMID:Increased susceptibility to LPS-induced endotoxin shock in secretory leukoprotease inhibitor (SLPI)-deficient mice. 1261 7

Cystic fibrosis is characterised in the lungs by high levels of neutrophil elastase (NE). NE induces interleukin-8 (IL-8) expression via an IL-1 receptor-associated kinase signalling pathway. Here, we show that these events involve the cell surface membrane bound toll-like receptor 4 (TLR4). We demonstrate that human embryonic kidney (HEK)293 cells transfected with a TLR4 cDNA (HEK-TLR4) express TLR4 mRNA and protein and induce IL-8 promoter activity in response to NE. Treatment of both HEK-TLR4 and human bronchial epithelial cells with NE decreases TLR4 protein expression. Furthermore, a TLR4 neutralising antibody abrogates NE-induced IL-8 production, and induces tolerance to a secondary lipopolysaccharide stimulus. These data implicate TLR4 in NE induced IL-8 expression in bronchial epithelium.
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PMID:Neutrophil elastase up-regulates interleukin-8 via toll-like receptor 4. 1278 2

Human beta-defensin-2 (HBD-2) gene expression is induced by tumour necrosis factor-alpha, interleukin-1beta and lipopolysaccharide. The objective of this study was to investigate the effect of neutrophil elastase (NE), a major pro-inflammatory protease, on HBD-2 expression. HBD-2 gene expression was assessed by reverse transcription polymerase chain reaction in the human bronchial epithelial cell line 16HBE14o- and primary normal human bronchial epithelial (NHBE) cells. Optimal HBD-2 expression was induced with 100 nM NE. Using a HBD-2-luciferase reporter construct, luciferase activity increased significantly in 16HBE14o- cells following incubation with NE. An increase in HBD-2 protein expression was observed in primary NHBE cells after incubation with NE as assessed by laser scanning cytometry. In conclusion, NE up-regulates HBD-2 expression in bronchial epithelial cells.
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PMID:Neutrophil elastase up-regulates human beta-defensin-2 expression in human bronchial epithelial cells. 1283 46

To reach the sites of inflammation, neutrophils traverse the endothelium, its underlying basement membrane, and other barriers depending on the localization of the insulting agent. Whether neutrophil elastase (NE) plays a role in neutrophil recruitment to inflamed sites is still debatable. By exploiting mice deficient in NE (NE(-/-)), we sought to address this dilemma. We recruited neutrophils to the lungs or the peritoneum of wild-type (WT) or NE(-/-) mice by intranasal or intraperitoneal challenge with Pseudomonas aeruginosa or its lipopolysaccharide. At designated times post-inoculation (0, 4, 24, and 48 h), groups of mice were killed to assess changes in leukocyte counts and inflammatory responses. NE(-/-) and WT mice had normal circulating leukocyte numbers including neutrophils and changes in the hemograms in the setting of acute inflammation were indistinguishable. Analyses of lung tissues or fluids from the lungs and peritoneum found that regardless of the inflammatory model, the leukocyte counts including neutrophils and the inflammatory response were similar in NE(-/-) and WT mice at all time points. In vitro, neutrophils isolated from the lungs or the peritoneum of NE(-/-) and WT mice had comparable chemotactic and respiratory-burst functions and migrated normally through Matrigel in response to various stimuli. Interestingly, preincubation of human peripheral blood neutrophils with NE physiologic inhibitors did not alter the migration of the cells through Matrigel. In sum, our findings present the first in vivo description that the absence of NE does not impair neutrophil recruitment to inflamed sites and that NE is not required for basement membrane transmigration of neutrophils.
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PMID:Deficiency in neutrophil elastase does not impair neutrophil recruitment to inflamed sites. 1456 40

An early response to cigarette smoke is an influx of leukocytes into the lung. Alveolar epithelial type II (ATII) cells may contribute by releasing chemokines in response to cigarette smoke and neutrophil elastase (NE). Human ATII cells were purified from normal regions of lungs resected for carcinoma (n = 14). In vitro, these cells exhibited ATII cell characteristics: lamellar bodies, apical microvilli, tight junctions, and expressed surfactant apoprotein C. Basal ATII cell release of five chemokines ranked as follows: monocyte chemotactic protein (MCP)-1 > interleukin (IL)-8 > growth-related oncogene (GRO)-alpha > macrophage inflammatory protein (MIP)-1alpha > regulated on activation, normal T cell expressed and secreted (RANTES). MIP-1alpha and RANTES were often not detectable. After stimulation with a mixture of lipopolysaccharide/endotoxin (LPS), tumor necrosis factor-alpha, IL-1beta, and IFN-gamma, MCP-1 and IL-8 secretion rose 4-6-fold, whereas GRO-alpha rose 25-fold. NE stimulated IL-8 mRNA expression, and 10nM NE stimulated IL-8 secretion; however, 100 nM NE caused a decrease in extracellular IL-8, MCP-1, and GRO-alpha, attributed to proteolysis. Cigarette smoke extract (CSE) inhibited IL-8 mRNA expression and release of all chemokines. Glutathione protected against the effects of CSE, suggesting oxidative mechanisms. GRO-alpha, important in growth and repair, was sensitive to both stimulation, by LPS:cytokines, and inhibition, by CSE. Thus, contrary to the original hypothesis, high concentrations of NE and CSE resulted in reduced extracellular chemokine levels. We hypothesize that reduced ATII cell-derived chemokine levels compromise alveolar repair, contributing to cigarette smoke-induced alveolar damage and emphysema.
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PMID:Primary human alveolar type II epithelial cell chemokine release: effects of cigarette smoke and neutrophil elastase. 1503 39

Antineutrophil cytoplasmic autoantibodies (ANCAs) recognizing human proteinase 3 of neutrophil granules are a diagnostic hallmark of Wegener granulomatosis, an autoimmune systemic vasculitis with predilection for the respiratory tract and kidneys. In vitro experiments have implicated several mechanisms by which ANCAs may lead to tissue injury. However, little is known about the pathogenic significance of proteinase 3-specific antibodies in vivo. In vivo models for ANCA-mediated proinflammatory effects have not been forthcoming, primarily because ANCA epitopes on human proteinase 3 are not shared by the murine homolog. In this study we generated ANCAs against recombinant murine proteinase 3 in proteinase 3/neutrophil elastase-deficient mice that recognized the murine antigen on the surface of neutrophils. Local inflammation induced by intradermal injection of tumor necrosis factor alpha triggered a stronger subcutaneous panniculitis in the presence of passively transferred systemic proteinase 3-ANCAs than in the presence of mock immune serum. When we transferred mouse proteinase 3-ANCA serum to systemically lipopolysaccharide-primed wild-type mice, mice treated with proteinase 3-ANCAs did not develop significantly stronger signs of inflammation of the lungs or kidneys than the respective mock immune serum-treated animals. In conclusion, our in vivo study provides the first evidence for a pathogenic effect of proteinase 3-specific ANCAs at local sites of inflammation.
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PMID:Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo. 1515 76

Secretory leucoprotease inhibitor (SLPI) is an anti-inflammatory antiprotease which can inhibit lipopolysaccharide-induced NF-kappaB activation. We examined its ability to inhibit NF-kappaB activation induced by lipoteichoic acid and investigated the effects of oxidation or complex formation with neutrophil elastase on SLPI's anti-inflammatory properties in U937 myelomonocytic cells and macrophages.
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PMID:Secretory leucoprotease inhibitor impairs Toll-like receptor 2- and 4-mediated responses in monocytic cells. 1515 85

Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used as a drug for patients with acute inflammatory disorders such as disseminated intravascular coagulation, shock, and pancreatitis in Japan. Recent studies have demonstrated that serine protease inhibitors may play an anti-inflammatory role beyond merely an inhibitory action on neutrophil elastase at the site of inflammation at least in vitro. To clarify the direct contributions of UTI to inflammatory condition in vivo, we analyzed its roles in experimental systemic inflammatory response induced by intraperitoneal administration of lipopolysaccharide (LPS) using UTI deficient (-/-) mice and corresponding wild-type (WT) mice. After LPS (1 mg/kg) challenge, UTI (-/-) mice revealed a significant elevation of plasma fibrinogen and fibrinogen/fibrin degradation products and a decrease in white blood cell counts compared with WT mice. LPS treatment induced more severe neutrophilic inflammation in the lung and the kidney obtained from UTI (-/-) mice than in those from WT mice, which was confirmed by histological examination. The protein levels of proinflammatory mediators, such as macrophage chemoattractant protein (MCP)-1 in the lungs, MCP-1 and keratinocyte chemoattractant (KC) in the kidneys, and interleukin-1beta, macrophage inflammatory protein-2, MCP-1, and KC in the liver, were significantly greater in UTI (-/-) mice than in WT mice after LPS challenge. Our results suggest that UTI protects against systemic inflammatory response and subsequent organ injury induced by bacterial endotoxin, at least partly through the inhibition of the enhanced expression of proinflammatory cytokines and chemokines.
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PMID:Urinary trypsin inhibitor protects against systemic inflammation induced by lipopolysaccharide. 1557 31

Neutrophil granulocytes are effector cells in innate and humoral immunity. They are involved in inflammatory processes by releasing pro-inflammatory enzymes, such as the human neutrophil elastase (HNE). We here report an optimisation of an HNE release assay using microplates. Special attention has been directed to overcome the often observed activation of neutrophils during isolation from fresh blood. This so-called basal stimulation can take place without addition of external stimulants and can cause severe problems during the assay. We demonstrated that bovine serum albumin (BSA), lipopolysaccharide (LPS), use of different blood donors, heparin and ethylenediaminetetraacetic acid (EDTA) do not cause basal stimulation, but may be due to mechanical stress and the immune system of the blood donor. Here, the number of eosinophils may play a role in the induction of activation. Basal stimulation was overcome when a hypertonic solution, such as sucrose- with N-(2-hydroxyethyl)-piperazine-N'-2-ethanesulfonic acid (HEPES) buffer, was used during centrifugation and the isolated granulocytes were left in phosphate buffered saline (PBS) for 30 min before stimulation. Sesquiterpene lactones (SLs), known for their anti-inflammatory activity were used for evaluation of the assay and were observed to inhibit HNE release at micromolar concentrations. Whereas N-formyl-methionyl-leucylphenylalanine (fMLP), platelet-activating factor (PAF) and basal stimulation resulted in similar IC50 values, phorbol-12-myristate-13-acetate (PMA) as a stimulant needed higher concentrations of SLs. The molecular inhibitory mechanism of SLs is discussed.
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PMID:Optimisation of a human neutrophil elastase assay and investigation of the effect of sesquiterpene lactones. 1609 62


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