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)

Mice injected with endotoxin develop endotoxaemia and endotoxin-induced death, accompanied by the oxidative burst and overproduction of inflammatory mediators. Lactoferrin, an iron binding protein, provides a natural feedback mechanism to control the development of such metabolic imbalance and protects against deleterious effects of endotoxin. We investigated the effects of intraperitoneal administration of human lactoferrin on lipopolysaccharide (LPS)-induced release of tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), interleukin 10 (IL-10) and nitric oxide (NO) in vivo. Lactoferrin was administered as a prophylactic, concurrent or therapeutic event relative to endotoxic shock by intravenous injection of LPS. Inflammatory mediators were measured in serum at 2, 6 and 18 h post-shock induction. Administration of lactoferrin 1 h before LPS resulted in a rather uniform inhibition of all mediators; TNF by 82%, IL-6 by 43%, IL-10 by 47% at 2 h following LPS injection,and reduction in NO (80%) at 6 h post-shock. Prophylactic administration of lactoferrin at 18 h prior to LPS injection resulted in similar decreases in TNF-alpha (95%) and in NO (62%), but no statistical reduction in IL-6 or IL-10. Similarly, when lactoferrin was administered as a therapeutic post-induction of endotoxic shock, significant reductions were apparent in TNF-alpha and NO in serum, but no significant effect was seen on IL-6 and IL-10. These results suggest that the mechanism of action for lactoferrin contains a component for differential regulation of cellular immune responses during in vivo models of sepsis.
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PMID:Differential effects of prophylactic, concurrent and therapeutic lactoferrin treatment on LPS-induced inflammatory responses in mice. 1229 49

Human lactoferrin (hLF) is an iron-binding glycoprotein involved in the innate host defense. The positively charged N-terminal domain of hLF mediates several of its activities by interacting with ligands such as bacterial lipopolysaccharide (LPS), specific receptors, and other proteins. This cationic domain is highly susceptible to limited proteolysis, which impacts on the affinity of hLF for the ligand. An analytical method, employing cation-exchange chromatography on Mono S, was developed to assess the N-terminal integrity of hLF preparations. The method, which separates N-terminally intact hLF from hLF species lacking two (Gly(1)-Arg(2)) or three (Gly(1)-Arg(2)-Arg(3)) residues, showed that 5-58% of total hLF in commercially obtained preparations was N-terminally degraded. The elution profile of hLF on Mono S unequivocally differed from lactoferrins from other species as well as homologous and other whey proteins. Analysis of fresh human whey samples revealed two variants of N-terminally intact hLF, but not limitedly proteolyzed hLF. Mono S chromatography of 2 out of 26 individual human whey samples showed a rare polymorphic hLF variant with three N-terminal arginines (Gly(1)-Arg(2)-Arg(3)-Arg(4)-Ser(5)-) instead of the usual variant with four N-terminal arginines (Gly(1)-Arg(2)-Arg(3)-Arg(4)-Arg(5)-Ser(6)-). In conclusion, Mono S cation-exchange chromatography appeared a robust method to assess the identity, purity, N-terminal integrity, and the presence of polymorphic and intact hLF variants.
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PMID:Analytical cation-exchange chromatography to assess the identity, purity, and N-terminal integrity of human lactoferrin. 1238 62

Lactoferrin is an iron-binding glycoprotein present in various secretions (eg. milk, tears, saliva,pancreatic juice, etc.). It is also stored in specific granules of polymorphonuclear granulocytes from which it is released following activation. Lactoferrin exerts a bactericidal activity by damaging the outermembrane of Gram-negative bacteria, as well as immunoregulatory functions by decreasing the release of interleukin-l (IL- 1), IL-2 and tumor necrosis factor-alpha INF-alpha) and enhancing monocyte and natural killer cell cytotoxicity. Lactoferrin binds with high affinity to lipid A, the toxic moiety of the lipopolysaccharide, or endotoxin from Gram-negative bacteria Lipopolysacchride interaction with monocytes/ma phages results in the production and release of TNF-alpha, that plays an important role in inducing septic shock In this respect, it has recently been demonstrated that lactoferrin inhibits the lipopolysaccharide interaction with CD14 on monocytes/macrophages by competition with the lipopolysaccharide binding protein. Therefore, besides its bactericidal activity, lactoferrin may also act by neutralizing the toxic effects of lipopolysaccharide and this protective role against endotoxin lethal shock has been demonstrated in animal models. Moreover, in vitro and in vivo neutralization of endotoxin by a human lactoferrin-derived peptide was also reported and lactoferrin or lactoferrin-derived peptides could represent useful tools for the treatment of endotoxin-induced septic hock. The recent production and characterization of monoclonal antibodies against different epitopes of human lactoferrin, including monoclonal antibodies selectively neutralizing lactoferrin binding to lipid A, may allow a better elucidation of the consequence of lactoferrin-lipopolysaccharide interaction.
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PMID:Antimicrobial and immunoregulatory functions of lactoferrin and its potential therapeutic application. 1254 52

The literature dealing with the biochemical basis of bacteriolysis and its role in inflammation, infection and in post-infectious sequelae is reviewed and discussed. Bacteriolysis is an event that may occur when normal microbial multiplication is altered due to an uncontrolled activation of a series of autolytic cell-wall breaking enzymes (muramidases). While a low-level bacteriolysis sometimes occurs physiologically, due to "mistakes" in cell separation, a pronounced cell wall breakdown may occur following bacteriolysis induced either by beta-lactam antibiotics or by a large variety of bacteriolysis-inducing cationic peptides. These include spermine, spermidine, bactericidal peptides defensins, bacterial permeability increasing peptides from neutrophils, cationic proteins from eosinophils, lysozyme, myeloperoxidase, lactoferrin, the highly cationic proteinases elastase and cathepsins, PLA2, and certain synthetic polyamino acids. The cationic agents probably function by deregulating lipoteichoic acid (LTA) in Gram-positive bacteria and phospholipids in Gram-negative bacteria, the presumed regulators of the autolytic enzyme systems (muramidases). When bacteriolysis occurs in vivo, cell-wall- and -membrane-associated lipopolysaccharide (LPS (endotoxin)), lipoteichoic acid (LTA) and peptidoglycan (PPG), are released. These highly phlogistic agents can act on macrophages, either individually or in synergy, to induce the generation and release of reactive oxygen and nitrogen species, cytotoxic cytokines, hydrolases, proteinases, and also to activate the coagulation and complement cascades. All these agents and processes are involved in the pathophysiology of septic shock and multiple organ failure resulting from severe microbial infections. Bacteriolysis induced in in vitro models, either by polycations or by beta-lactams, could be effectively inhibited by sulfated polysaccharides, by D-amino acids as well as by certain anti-bacteriolytic antibiotics. However, within phagocytic cells in inflammatory sites, bacteriolysis tends to be strongly inhibited presumably due to the inactivation by oxidants and proteinases of the bacterial muramidases. This might results in a long persistence of non-biodegradable cell-wall components causing granulomatous inflammation. However, persistence of microbial cell walls in vivo may also boost innate immunity against infections and against tumor-cell proliferation. Therapeutic strategies to cope with the deleterious effects of bacteriolysis in vivo include combinations of autolysin inhibitors with combinations of certain anti-inflammatory agents. These might inhibit the synergistic tissue- and- organ-damaging "cross talks" which lead to septic shock and to additional post-infectious sequelae.
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PMID:The role of bacteriolysis in the pathophysiology of inflammation, infection and post-infectious sequelae. 1258 16

In patients with diarrhea caused by Vibrio parahaemolyticus, antibody-secreting cell responses to thermostable direct hemolysin (TDH), lipopolysaccharide (LPS), and whole-cell bacteria were seen. TDH- and LPS-specific responses were seen in serum samples, and immunoglobulin A antibody responses were observed in stool. Levels of C-reactive protein and nitric oxide metabolites increased in the systemic circulation at the onset of illness. Tumor necrosis factor-alpha and lactoferrin levels were high during the acute stage in mucosal secretions and in plasma, whereas interleukin-1beta levels were high only in mucosal secretions. Duodenal and rectal biopsy specimens obtained at the onset of illness showed an acute inflammatory response. The lamina propria showed edema, congestion of blood vessels, and hemorrhage, with an increase in levels of polymorphonuclear neutrophils and macrophages. Strains belonging to different serotypes exhibited varying resistance to killing by serum; the O8:K21 strain was most sensitive. Infection with V. parahaemolyticus results in B cell responses and an acute inflammatory response that is self-limiting.
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PMID:Adaptive and inflammatory immune responses in patients infected with strains of Vibrio parahaemolyticus. 1266 Sep 23

Cationic antibacterial peptides are potentially therapeutic in the treatment of sepsis, because of their amalgamated antibacterial and lipopolysaccharide-binding activities. We prepared acyl analogues of the peptide fragment of human lactoferrin, which originally had weak antibacterial activity. It was found that 12 carbon units constitute the optimal acyl chain length, enhancing the antibacterial activity and binding of lipopolysaccharide by up to two orders of magnitude. Lactoferrin-based lipopeptides approached the activity of polymyxin B, a lipopeptide of natural origin, but were also active against Gram-positive bacteria.
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PMID:Enhancement of antibacterial and lipopolysaccharide binding activities of a human lactoferrin peptide fragment by the addition of acyl chain. 1269 47

Lactoferricin (LFcin) was initially identified as an antimicrobial peptide derived by pepsin digestion of lactoferrin (LF), a multifunctional innate-defense protein in milk. Various synthetic analogs of LFcin have also been reported. LFcin inhibits a diverse range of microorganisms such as gram-negative bacteria, gram-positive bacteria, yeast, filamentous fungi, and parasitic protozoa, including some antibiotic-resistant pathogens. LFcin kills target organisms by membrane perturbation and acts synergistically with some antimicrobial agents. LFcin exhibits numerous biological activities in common with those of LF. Whereas LFcin suppresses the activation of innate immunity by microbial components such as lipopolysaccharide (LPS) and CpG DNA, the peptide itself activates immunity. Administration of LFcin analogs has been shown to protect the host via direct antimicrobial activity and immunostimulatory effects in several infection models of mice. Here we present a comprehensive review of investigations of LFcin and related peptides.
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PMID:Lactoferricin derived from milk protein lactoferrin. 1276 36

Proinflammatory cytokines released from monocytes/macrophages, in particular tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, and IL-8 seem to play an important role in Inflammatory Bowel Disease (ulcerative colitis and Crohn's disease). Endotoxins or lipopolysaccharides, derived from the outer membrane of Gram-negative bacteria interact with CD14 on surface membrane of macrophages, thus triggering a signal cascade, which leads to the production and release of proinflammatory cytokines, particularly TNF-alpha. Therefore, in IBD, lipopolysaccharides could play a pathogenic role. In this respect, plasma endotoxins have been demonstrated in a not negligible percentage of patients with ulcerative colitis and in their unaffected relatives. The presence of circulating endotoxins could be due, at least in part, to the impaired natural immunity in either patients with ulcerative colitis or in their first degree unaffected relatives. Lactoferrin is an iron-binding glycoprotein, which binds to the lipid A region of lipopolysaccharide with a high affinity and this interaction prevents the binding of lipopolysaccharide to CD14, thus inhibiting the release of proinflammatory cytokines. Therefore, based on the possible pathogenic role exerted by endotoxins in ulcerative colitis, lactoferrin may deserve attention as a possible therapeutical agent in experimental models of Inflammatory Bowel Disease.
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PMID:Immune abnormalities and endotoxemia in patients with ulcerative colitis and in their first degree relatives: attempts at neutralizing endotoxin-mediated effects. 1287 Nov 78

Innate host defence, involving both cellular and humoral mediators, is a prominent function of the human airways. Cellular mediators of innate immunity include dendritic cells, natural killer cells, cytotoxic T cells, macrophages and neutrophils, while humoral mediators of innate immunity consist of components of the epithelial lining fluid (ELF) covering the airways. Microbicidal substances in the ELF can selectively disrupt bacterial cell walls and membranes, sequester microbial nutrients or act as decoys for microbial attachment. Antimicrobial components of airway secretions include lysozymes, lactoferrin, secretory leukoprotease inhibitor, defensins and cathelicidins. Defensins are the most widely studied family of antimicrobial peptides present in airway fluid. Humans produce at least 10 different defensin molecules, six alpha-defensins and four beta-defensins similar in structure and function. Direct evidence that defensins have central roles in host defense has only recently become available. Some defensins and defensin-like molecules could serve as templates for the development of pulmonary pharmaceuticals. As potential therapeutics, they possess several desirable properties, including the ability to kill a broad spectrum of micro-organisms while permitting little development of microbial resistance. Many peptides can also neutralize effects of lipopolysaccharide on macrophages and other host defense cells and decrease the release of proinflammatory cytokines thereby giving protection against septic shock. Protegrin-1 is a minidefensin isolated from pig leukocytes and has proved to be an attractive template for large-scale development of antibacterials. One such protegrin analog, iseganan is in phase III clinical trials for the treatment of oral mucositis secondary to systemic chemotherapy. Other prospective uses of iseganan include control of respiratory pathogens in patients with cystic fibrosis and reduction of oral bacteria to prevent ventilator-associated pneumonia. However, in order to advance the production and clinical testing of peptide-based therapeutics, technical hurdles of synthesizing large quantities of complexly folded peptides must be first overcome. Strategies to develop potent peptide-based microbicides are promising in the struggle against increasingly resistant pathogens.
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PMID:The role of defensins in lung biology and therapy. 1472 45

During mammary gland infection, non-specific responses are the predominant ones. The goal of this study was to investigate the mRNA expression of various soluble immune components and of the major milk proteins during the acute phase of mammary inflammation. Five healthy lactating cows were intramammary infused in one quarter with 100 microg Escherichia coli-endotoxin (lipopolysaccharide, LPS) and the contralateral quarter with saline (9 g/l) serving as control. Mammary biopsy samples of both quarters were taken immediately before and at 3, 6, 9 and 12 h after infusion and mRNA expression of various factors was quantified via real-time RT-PCR. Blood samples for determination of leukocyte number were taken simultaneously with the biopsy samples and rectal temperature was measured at 1-h intervals. Rectal temperature increased until 5h (P < 0.05) after LPS administration and remained elevated until 9 h after LPS inoculation. Blood leukocyte number decreased (P < 0.05) from 0 to 3 h from 7.7 +/- 1.1 x 10(9)l(-1) to 5.7 +/- 1.0 x 10(9)l(-1) and thereafter recovered to pre-treatment levels until 12 h after LPS challenge. In LPS-treated quarters, tumor necrosis factor-alpha and cyclooxygenase-2-mRNA expression increased (P < 0.05) to highest values at 3h after LPS challenge. Lactoferrin, lysozyme, inducible nitric oxide synthase increased (P < 0.05) and peaked at 6 h after challenge, and platelet-activating factor acetylhydrolase-mRNA expression tended to increase (P = 0.07). mRNA expression of insulin-like growth factor-I and of alphaS1-casein (CN), alphaS2-CN, beta-CN and beta-lactoglobulin did not change significantly, whereas mRNA expression of 5-lipoxygenase and alpha-lactalbumin decreased (P < 0.05) in both quarters and that of kappa-CN only in the LPS quarter. mRNA expression of some investigated factors (tumor necrosis factor-alpha, lysozyme, 5-lipoxygenase, alpha-lactalbumin) changed in control quarters, however in all respective factors less than in the LPS quarters (P < 0.05). In conclusion, mRNA expression of most inflammatory factors increased within hours, whereas that of most milk proteins remained unchanged.
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PMID:Short-term changes of mRNA expression of various inflammatory factors and milk proteins in mammary tissue during LPS-induced mastitis. 1475 84


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