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)

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

1. Various chemokines, such as keratinocyte chemoattractant (KC), macrophage inflammatory protein (MIP)-1alpha and macrophage chemoattractant protein (MCP)-1, are involved in the pathogenesis of acute lung injury induced by bacterial endotoxin (lipopolysaccharide; LPS). Oxidative stress is an important regulator of the expression of these chemokines, whereas vitamin E protects against LPS-induced insults. In the present study, we determined the effects of 2-(alpha-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol (TMG), a novel water-soluble vitamin E derivative with excellent anti-oxidant activity, on acute lung injury induced by intratracheal instillation of LPS (125 micro g/kg) in mice. 2. When TMG was administered intratracheally and intravenously (0.1, 1.0 or 10 mg/kg), it dose-dependently decreased the infiltration of neutrophils into bronchoalveolar lavage fluid after LPS challenge. 3. Histological examination showed that treatment with TMG ameliorated the LPS-induced infiltration of neutrophils into the lungs. Furthermore, TMG attenuated the LPS-induced increase in pulmonary expression of KC, MIP-1alpha and MCP-1 at both the transcriptional and translational levels. 4. These results indicate that TMG is a possible treatment for acute lung injury, especially that caused by Gram-negative bacteria. The therapeutic effect of TMG may be mediated, at least in part, by suppression of the local expression of chemokines, possibly through its strong anti-oxidant activity.
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PMID:A novel water-soluble vitamin E derivative prevents acute lung injury by bacterial endotoxin. 1505 18

The use of chronic glucocorticoid (GC) therapy for the treatment of inflammatory diseases is limited by associated metabolic side effects, including muscle atrophy. Therefore, selective glucocorticoid receptor-(GR)-binding ligands that maintain anti-inflammatory activity and demonstrate diminished side-effect profiles would have great therapeutic utility. In this work, we use Taqman PCR and ELISA methods to show that GCs can inhibit basal, and lipopolysaccharide (LPS)-stimulated levels of cytokines IL-6 and TNFalpha, and also the chemokine MCP-1 in a non-inflammatory system such as primary human skeletal muscle cells. In the murine C2C12 skeletal muscle cell line we observe a similar effect of GCs on IL-6 and MCP-1; however, in contrast to previous reports, we observe a time-dependent repression of TNFalpha. Furthermore, in skeletal muscle cells, concomitant with cytokine repression, GCs transcriptionally induce glutamine synthetase (GS), a marker for muscle wasting, in an LPS independent manner. Similarly, administration of dexamethasone to mice, previously administered LPS, results in an increase in GS and an inhibition of TNFalpha and MCP-1 in skeletal muscle tissue. Thus, skeletal muscle cells and tissues present a novel system for the identification of selective GR-binding ligands, which simultaneously inhibit cytokine expression in the absence of GS induction.
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PMID:Skeletal muscle: a dual system to measure glucocorticoid-dependent transactivation and transrepression of gene regulation. 1508 51

An exaggerated pro-inflammatory response in endotoxemia may lead to multiple organ damage including acute lung injury. Heat stress prior to endotoxemia results in attenuation of inflammation possibly by decreasing cytokine production. Monocyte chemoattractant protein (MCP)-1, a pro-inflammatory cytokine, is responsible for monocyte recruitment into the lung in acute lung injury. The objective of this study is to determine if pretreatment with heat results in decreased MCP-1 production in the lungs of endotoxemic rats at a transcriptional or post-transcriptional level. Rats were assigned to one of four groups: control, heat alone, heat with or without endotoxin. Rats were made endotoxemic by injection of Escherichia coli lipopolysaccharide. MCP-1 was measured in lavage fluid and MCP-1 mRNA in the lung tissue. Endotoxemia resulted in production of MCP-1. Control and heat alone rats had 21+/-4 vs. 20+/-3 pg/ml, p=0.75. MCP-1 concentration was decreased in the lavage fluid of pre-heated when compared to non-heated endotoxemic rats (37+/-28 vs. 70+/-35 pg/ml, p <0.02 ). However, the MCP-1 mRNA was higher in the heated compared to non-heated endotoxemic rats (1.59+/-0.35 vs. 0.74+/-0.51, MCP-1/beta-actin mRNA, p <0.01). Control and heat alone rats had undetectable mRNA MCP-1 in the lungs. Heat stress prior to endotoxemia results in decreased production of MCP-1 by a post-transcriptional mechanism.
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PMID:Heat stress decreases pulmonary MCP-1 production in endotoxemia. 1518 41

Bacillus anthracis lethal toxin (LT) produces symptoms of anthrax in mice and induces rapid lysis of macrophages (M phi) derived from certain inbred strains. We used nine inbred strains and two inducible nitric oxide synthase (iNOS) knockout C57BL/6J strains polymorphic for the LT M phi sensitivity Kif1C locus to analyze the role of M phi sensitivity (to lysis) in LT-mediated cytokine responses and lethality. LT-mediated induction of cytokines KC, MCP-1/JE, MIP-2, eotaxin, and interleukin-1 beta occurred only in mice having LT-sensitive M phi. However, while iNOS knockout C57BL/6J mice having LT-sensitive M phi were much more susceptible to LT than the knockout mice with LT-resistant M phi, a comparison of susceptibilities to LT in the larger set of inbred mouse strains showed a lack of correlation between M phi sensitivity and animal susceptibility to toxin. For example, C3H/HeJ mice, harboring LT-sensitive M phi and having the associated LT-mediated cytokine response, were more resistant than mice with LT-resistant M phi and no cytokine burst. Toll-like receptor 4 (Tlr4)-deficient, lipopolysaccharide-nonresponsive mice were not more resistant to LT. We also found that CAST/Ei mice are uniquely sensitive to LT and may provide an economical bioassay for toxin-directed therapeutics. The data indicate that while the cytokine response to LT in mice requires M phi lysis and while M phi sensitivity in the C57BL/6J background is sufficient for BALB/cJ-like mortality of that strain, the contribution of M phi sensitivity and cytokine response to animal susceptibility to LT differs among other inbred strains. Thus, LT-mediated lethality in mice is influenced by genetic factors in addition to those controlling M phi lysis and cytokine response and is independent of Tlr4 function.
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PMID:Mouse susceptibility to anthrax lethal toxin is influenced by genetic factors in addition to those controlling macrophage sensitivity. 1527 1

Molecular and genetic studies have demonstrated that members of the Toll-like receptor (TLR) family are critical innate immune receptors. TLRs are recognition receptors for a diverse group of microbial ligands including bacteria, fungi, and viruses. This study demonstrates that distinct TLRs are responsible for the recognition of Helicobacter lipopolysaccharide (LPS) versus intact Helicobacter bacteria. We show that the cytokine-inducing activity of Helicobacter LPS was mediated by TLR4; i.e., TLR4-deficient macrophages were unresponsive to Helicobacter pylori LPS. Surprisingly, the cytokine response to whole Helicobacter bacteria (H. pylori, H. hepaticus, and H. felis) was mediated not by TLR4 but rather by TLR2. Studies of HEK293 transfectants revealed that expression of human TLR2 was sufficient to confer responsiveness to intact Helicobacter bacteria, but TLR4 transfection was not sufficient. Our studies further suggest that cag pathogenicity island genes may modulate the TLR2 agonist activity of H. pylori as cagA+ bacteria were more active on a per-cell basis compared to cagA mutant bacteria for interleukin-8 (IL-8) cytokine secretion. Consistent with the transfection studies, analysis of knockout mice demonstrated that TLR2 was required for the cytokine response to intact Helicobacter bacteria. Macrophages from both wild-type and TLR4-deficient mice produced a robust cytokine secretion response (IL-6 and MCP-1) when stimulated with intact Helicobacter bacteria. In contrast, macrophages from TLR2-deficient mice were profoundly unresponsive to intact Helicobacter stimulation, failing to secrete cytokines even at high (100:1) bacterium-to-macrophage ratios. Our studies suggest that TLR2 may be the dominant innate immune receptor for recognition of gastrointestinal Helicobacter species.
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PMID:Intact gram-negative Helicobacter pylori, Helicobacter felis, and Helicobacter hepaticus bacteria activate innate immunity via toll-like receptor 2 but not toll-like receptor 4. 1550 75

Exposure of the respiratory tract to lipopolysaccharide (LPS) induces acute local inflammation and tissue injury associated with the various deliveries of LPS. To determine potential association of local inflammatory responses with respiratory tract dysfunction, infiltration of inflammatory cells, production of inflammatory mediators, lung hyperinflation and edema were measured in Wister rats 2, 4, and 24 h after an intratracheal administration of LPS at different doses (5, 50, 500 and 5000 microg/ml/kg). Lung hyperinflation determined by an increased excised lung gas volume was significantly increased 2 and 4 h after LPS instillation and lung edema occurred from 2 h onward. Peak BAL levels of TNFalpha appeared at 2 h, MCP-1 at 4 h, and IL-6 at 2 and 4 h, while BAL levels of IL-1beta were increased during 24 h after the intratracheal instillation of LPS. Neutrophilia in BAL fluid was noted from 2 h post-challenge. Our results demonstrate a clear dose-related change in the lung weight at 4 and 24 h, in the BAL levels of MCP-1 at 4 h, and IL-6 and IL-1beta at 2 and 4 h. It seems important to understand polymorphisms of LPS-induced lung hyperinflation and inflammation. Lung hyperinflation and inflammation may be independent during the development of acute lung injury.
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PMID:Lung inflammatory responses and hyperinflation induced by an intratracheal exposure to lipopolysaccharide in rats. 1552 55

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

Blood neutrophils (PMN) are usually unresponsive to CC chemokines such as monacyte chemotactic protein-1 and macrophage inflammatory protein-1 alpha. In rodents, the lung buildup of PMN as determined by myeloperoxidase (MPO) activity after airway instillation of bacterial lipopolysaccharide (LPS) was independent of MCP-1 and MIP-1 alpha. In striking contrast, during sepsis following cecal ligation and puncture (CLP), blood PMN demonstrated mRNA for CC chemokine receptors. Furthermore, PMN from CLP, but not from sham rodents, bound MCP-1 and MIP-1 alpha and responded chemotactically in vitro to both MCP-1 and MIP-1 alpha. In CCR2(-/-) mice or WT mice treated in vivo with antibodies to either MCP-1 or MIP-1 alpha, MPO activity was greatly attenuated in CLP animals. In CLP mice, increased serum IL-6 levels were found to be dependent on CCR2, MCP-1, and MIP-1 alpha. When PMN from CLP rodents were incubated in vitro with either MCP-1 or MIP-1 alpha, release of IL-6 was also shown. These findings suggest that sepsis fundamentally alters the trafficking of PMN into the lung in a manner that now engages functional responses to CC chemokines.
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PMID:Novel chemokine responsiveness and mobilization of neutrophils during sepsis. 1557 60

Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31), an adhesion molecule expressed on hematopoietic and endothelial cells, mediates apoptosis, cell proliferation, and migration and maintains endothelial integrity in addition to its roles as a modulator of lymphocyte and platelet signaling and facilitator of neutrophil transmigration. Recent data suggest that CD31 functions as a scaffolding protein to regulate phosphorylation of the signal transducers and activators of transcription (STAT) family of signaling molecules, particularly STAT3 and STAT5. STAT3 regulates the acute phase response to innate immune stimuli such as lipopolysaccharide (LPS) and promotes recovery from LPS-induced septic shock. Here we demonstrate that CD31-deficient mice have reduced survival during endotoxic LPS-induced shock. As compared to wild-type controls, CD31-deficient mice showed enhanced vascular permeability; increased apoptotic cell death in liver, kidney, and spleen; and elevated levels of serum tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFNgamma), MCP-1, MCP-5, sTNRF, and IL-6. In response to LPS in vivo and in vitro, splenocytes and endothelial cells from knockout mice had reduced levels of phosphorylated STAT3. These results suggest that CD31 is necessary for maintenance of endothelial integrity and prevention of apoptosis during septic shock and for STAT3-mediated acute phase responses that promote survival during septic shock.
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PMID:Enhanced susceptibility to endotoxic shock and impaired STAT3 signaling in CD31-deficient mice. 1563 11


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