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PubMed1998

Effect of lipopolysaccharide on the permeability and reactivity of the cerebral microcirculation: role of inducible nitric oxide synthase.

The goal of this study was to examine the effect of lipopoly saccharide on the permeability of the blood-brain barrier and reactivity of cerebral arterioles. We examined the pial microcirculation in rats using intravital fluorescence microscopy. Permeability of the blood-brain barrier (clearance of fluorescent-labeled dextran; molecular weight 10,000 Da; FITC-dextran-10K) and diameter of pial arterioles were measured in the absence and presence of topical application of vehicle (saline) or lipopolysaccharide (200 ng/ml). During superfusion with vehicle, clearance of FITC-dextran-10K from pial vessels was minimal, and diameter of pial arterioles remained constant. Topical application of lipopolysaccharide (200 ng/ml) produced an increase in clearance of FITC-dextran-10K and dilated pial arterioles. To determine whether lipopolysaccharide-induced changes in permeability of the blood-brain barrier and dilatation of cerebral arterioles was related to the synthesis/release of inducible nitric oxide, we examined the effects of aminoguanidine (0.5 mM). Aminoguanidine inhibited lipopolysaccharide-induced increases in permeability of the blood-brain barrier and dilatation of cerebral arterioles. The findings of the present study suggest that lipopolysaccharide increases permeability of the blood-brain barrier and diameter of pial arterioles via the activation of inducible nitric oxide synthase.

Animals↗

PubMed2001

L-citrulline mediated relaxation in the control and lipopolysaccharide-treated rat aortic rings.

The present study was undertaken to investigate relaxant effect of L-citrulline in phenylephrine precontracted endothelium intact thoracic aortic rings obtained from control or lipopolysaccharide (1 mg/kg)-treated rats. L-citrulline produced 40+/-3% (n=36) and 60+/-5% (n=24) relaxations in control and lipopolysaccharide-treated rings, respectively. Nitric oxide (NO) release and cyclic guanosine-3',5'-monophosphate levels from the rings were also increased following treatment with L-citrulline. Inhibition of guanylate cyclase, L-citrulline recycling to L-arginine or denudation of the endothelium, significantly reduced L-citrulline-induced relaxations both in control and lipopolysaccharide-treated rings. Treatment of rings with protein synthesis inhibitors prevented relaxations to L-citrulline. Inhibitor of Ca2+-activated K+ channels, tetrabutylammonium or precontraction of the rings with KCl (80 mM), significantly attenuated L-citrulline mediated relaxations in control and lipopolysaccharide-treated rings. Thus, L-citrulline seems to exert significant relaxation by supplementing the release of NO due to its recycling to L-arginine, which gets further augmented after lipopolysaccharide treatment.

Animals↗

PubMed1996

Vitamin C and E prevent lipopolysaccharide-induced apoptosis in human endothelial cells by modulation of Bcl-2 and Bax.

Lipopolysaccharide induced apoptosis and necrosis of human umbilical venous endothelial cells in a time-dependent manner. Lipopolysaccharide (1 microgram/ml)-induced apoptosis was maximal after 18 h, whereas necrosis occurred after prolonged incubation for more than 24 h. The increase in apoptosis correlated with a reduction in Bcl-2, a potent cell death inhibitor. Furthermore, lipopolysaccharide treatment upregulated Bax, which heterodimerizes with and thereby inhibits Bcl-2. Both the antioxidant N-acetylcysteine and the combination of vitamin C and E (10 microM) completely inhibited lipopolysaccharide-induced apoptosis, whereas vitamin C or E alone was less effective. The reduction of lipopolysaccharide-induced apoptosis by vitamin C and E was paralleled by an increase in Bcl-2 and a decrease in Bax protein levels. Thus, vitamin C and E seem to interfere with the Bcl-2 family of apoptosis regulators in human umbilical venous endothelial cells.

Acetylcysteine↗

PubMed1999

Interactions of an antimicrobial peptide, magainin 2, with lipopolysaccharide-containing liposomes as a model for outer membranes of gram-negative bacteria.

F12W-magainin 2 preferentially interacted with lipopolysaccharide-containing bilayers, permeabilizing the membranes, compared with lipopolysaccharide-free phosphatidylcholine vesicles. Using this system, we demonstrated for the first time that the magainin peptide forms a helix upon binding to lipopolysaccharide. Incorporation of lipid A into phosphatidylcholine liposomes also enhanced interactions with the peptide. The presence of Mg2+, which nullifies the peptide's antibacterial activity against gram-negative bacteria, again weakened the interactions between the peptide and lipopolysaccharide-doped bilayers. This system seems to be useful for investigating the molecular details of peptide-lipopolysaccharide interactions.

Amino Acid Sequence↗

PubMed2001

Excretory/secretory products from plerocercoids of Spirometra erinaceieuropaei suppress gene expressions and production of tumor necrosis factor-alpha in murine macrophages stimulated with lipopolysaccharide or lipoteichoic acid.

We previously reported that the ES products from the plerocercoids of Spirometra erinaceieuropaei reduce nitric oxide synthase and chemokine gene expression in macrophages. In this study, we show that ES products suppressed tumor necrosis factor-alpha mRNA expression and tumor necrosis factor-alpha production in murine peritoneal macrophages stimulated with lipopolysaccharide or lipoteichoic acid in vitro. When macrophages from ES product-injected mice were stimulated with lipopolysaccharide in vitro, these cells produced smaller amounts of tumor necrosis factor-alpha compared with those taken from control mice. The suppressive effects of ES products were not restored by the treatment of indomethacin or anti-IL-10 antibody, and the ES products did not induce mRNA expression of secretory leukocyte protease inhibitor. Macrophages from C3H/HeJ mice, which have a single point mutation in the Toll-like receptor 4 gene, expressed tumor necrosis factor-alpha and IL-1alpha mRNA in the presence of lipopolysaccharide, but these expressions were less than those of macrophages from C3H/HeN. ES products significantly suppressed tumor necrosis factor-alpha gene expression and tumor necrosis factor-alpha production in macrophages from C3H/HeN and C3H/HeJ mice stimulated with lipopolysaccharide. However, ES products had no effect on IL-1 mRNA expression. Our data suggest that the plerocercoids secrete the tumor necrosis factor-alpha inhibitory products to evade the host's immune system, and that tumor necrosis factor-alpha mRNA expression might be inhibited downstream from Toll-like receptor 4 in the lipopolysaccharide signaling pathway.

Animals↗

PubMed1998

Macromolecular leakage beneath full cast crowns. Part III: The diffusion of lipopolysaccharide and dextran.

STATEMENT OF PROBLEM: Most microleakage studies have used low molecular weight dyes or isotopes rather than clinically relevant materials, such as lipopolysaccharides or cell wall materials, that have been shown to provoke inflammatory reactions in the dental pulp. PURPOSE: This study evaluated the leakage (diffusion) of lipopolysaccharide and dextran beneath cast gold crowns luted with 3 cements. MATERIALS AND METHODS: Thirty extracted molars were prepared for crowns. Ten crowns with access ports (facial or lingual) were cast in gold and luted with zinc phosphate, glass ionomer, and an adhesive resin cement onto their preparations. Teeth and crowns with filters inserted into the ports were immersed in a solution of labeled macromolecules (TRITC-LPS, FITC-dextran) and evaluated for leakage at 2 weeks, and 1, 2, 3, 4, 5, and 6 months. Filters were retrieved and analyzed with fluorescent microscopy. RESULTS: All filters retrieved from crowns luted with zinc phosphate, glass ionomer, and adhesive resin cements demonstrated no detectable leakage and were negative for both FITC-dextran and TRITC-lipopolysaccharide at all evaluation periods. CONCLUSION: Leakage of lipopolysaccharides and dextran did not occur during the period of this study. For the length of this investigation, zinc phosphate, Ketac-Cem, and C&B-Metabond were equally effective at preventing leakage of detectable molecular concentrations of lipopolysaccharide and dextran to the level of the access ports.

Crowns↗

PubMed1999

Nitric oxide mediates the lipopolysaccharide dependent upregulation of the heme oxygenase-1 gene expression in cultured rat Kupffer cells.

BACKGROUND/AIMS: Heme oxygenase catalyzes the rate-limiting enzymatic step of heme degradation. The inducible isoform of heme oxygenase, heme oxygenase-1, is expressed at a low level in most tissues and is upregulated by its substrate heme and various stress stimuli. Kupffer cells which represent the largest population of the body's tissue macrophages serve physiological functions in the defense against various pathogens such as lipopolysaccharide. The goal of the present study was to investigate the heme oxygenase-1 gene expression in Kupffer cells of rat liver and in isolated Kupffer cell cultures during treatment with lipopolysaccharide. METHODS: Cryostat sections of normal rat liver were investigated by immunofluorescence double-staining using specific antibodies for rat heme oxygenase-1 and ED2. Isolation and cell culture of Kupffer cells and primary hepatocytes from rat liver, as well as Northern and Western blot analysis, were performed with standard protocols. RESULTS: Heme oxygenase-1 protein was highly expressed in large sinusoidal cells of normal rat liver, which were identified as Kupffer cells by staining with the macrophage surface marker ED2. By contrast, no expression of heme oxygenase-1 was detected in liver parenchymal cells. High expression of heme oxygenase-1 was also found in isolated Kupffer cells in culture by immunocytochemical staining as well as by Western and Northern blot analysis. After treatment of Kupffer cells cultures with lipopolysaccharide, heme oxygenase-1 was upregulated on the protein and mRNA level in a time- and dose-dependent manner. This increase in heme oxygenase-1 expression by lipopolysaccharide was prevented by the nitric oxide inhibitor N(G)-monomethyl-L-arginine which was reversed by an excess of L-arginine. Various nitric oxide donors up-regulated heme oxygenase-1 mRNA expression in Kupffer cells. CONCLUSIONS: The lipopolysaccharide-dependent upregulation of the heme oxygenase-1 gene which is highly expressed in Kupffer cells is mediated by a nitric oxide-dependent mechanism.

Animals↗

PubMed1999

Suppression of gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide by sulglycotide.

The effect of the antiulcer agent sulglycotide on gastric epithelial cell apoptosis and the expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-4 (IL-4) during Helicobacter pylori lipopolysaccharide-induced acute gastritis was investigated. Rats, pretreated twice daily for 3 consecutive days with sulglycotide at 200 mg/kg or vehicle, were subjected to surface epithelial application of H. pylori lipopolysaccharide (50 microg/animal), and, after 4 additional days on the drug or vehicle regimen, their mucosal tissue was used for histologic assessment, quantitation of TNF-alpha and IL-4, and the assay of epithelial cell apoptosis. In the absence of sulglycotide, H. pylori lipopolysaccharide caused acute mucosal responses manifested by the inflammatory infiltration of the lamina propria with lymphocytes and plasma cells, edema, hyperemia, and epithelial hemorrhage. These responses were accompanied by an 11-fold increase in epithelial cell apoptosis and a 9-fold enhancement of the mucosal expression of proinflammatory cytokine TNF-alpha. However, the mucosal expression of regulatory cytokine IL-4 decreased by 15%. Treatment with sulglycotide produced significant (56.6%) reduction in the extent of acute mucosal inflammatory changes caused by H. pylori lipopolysaccharide. Moreover, the effect of sulglycotide was manifested in an 88.3% reduction in the epithelial cell apoptosis and a 69.1% decrease in the mucosal expression of TNF-alpha, whereas the expression of IL-4 showed only marginal (6%) enhancement. The results suggest that the cytoprotective agent sulglycotide suppresses the inflammatory and apoptotic events elicited in gastric mucosa by H. pylori lipopolysaccharide through stimulation of TNF-alpha expression.

Animals↗

PubMed2002

A single lipopolysaccharide administration is sufficient to induce a long-term desensitization of the hypothalamic-pituitary-adrenal axis.

We have previously shown that a single exposure of adult rats to a severe emotional stressor such as immobilization is able to exert a long-term desensitization of the response of the hypothalamic-pituitary-adrenal (HPA) axis to the same stimulus when applied days to weeks later. Surprisingly, the intensity of the effect increased with time elapsed between the two exposures, suggesting that we are dealing with a new type of stress-associated phenomenon. Taking into account the clinical importance of tolerance to endotoxin, in the present study we assessed whether a single exposure to an immunological stressor such as lipopolysaccharide can induce effects similar to those of immobilization. Rats injected with lipopolysaccharide (1 mg/kg) showed a reduction of the response of the corticotropin-releasing factor mRNA in the paraventricular nucleus of the hypothalamus after a new lipopolysaccharide injection 4, but not 2 weeks later. In an additional experiment using a different blood sampling procedure, adrenocorticotropin hormone, corticosterone and tumor necrosis factor-alpha responses were reduced approximately to the same extent by previous experience with lipopolysaccharide either 1 or 4 weeks before. Our data suggest that a previous single exposure to lipopolysaccharide induces a long-lasting tolerance of the HPA axis that likely involves some kind of learning-like brain plasticity.

Adrenocorticotropic Hormone↗

PubMed1998

Time course and localization patterns of interleukin-1beta messenger RNA expression in brain and pituitary after peripheral administration of lipopolysaccharide.

The inflammatory cytokine interleukin-1 has been implicated as a mediator of many centrally controlled responses, such as fever and increased activity of the hypothalamic-pituitary adrenal axis, after systemic infections. To identify the neuroanatomical loci of brain interleukin-1-producing cells during infection, we investigated interleukin-1beta messenger RNA expression by in situ hybridization histochemistry using a 500 nt ribonucleotide probe applied on brain sections from rats injected intraperitoneally with 2.5 mg/kg bacterial lipopolysaccharide or saline. In control animals, interleukin-1beta messenger RNA was not detectable. In the brains of lipopolysaccharide-injected animals, two temporally and spatially distinct waves of interleukin-1beta messenger RNA induction were observed. First, cell labelling appeared at 0.5 h, peaked at 2 h, and declined at 4-8 h. The labelled cells were concentrated in circumventricular organs--organum vasculosum of the lamina terminalis, subfornical organ, median eminence, and area postrema--and in choroid plexus, meninges, and blood vessels. Second, at 8-12 h, scattered small cells became labelled throughout the entire brain parenchyma; the labelling subsided by 24 h. Labelling was not observed in any neurons. In the pituitary, lipopolysaccharide induced strong interleukin-1beta messenger RNA expression initially in the anterior lobe at 0.5-1 h, and later in the neural lobe at 1-2 h, and subsiding thereafter. The results show that at early time points, peripheral lipopolysaccharide induces interleukin-1beta message production at the blood brain barrier and in circumventricular organs where the blood brain barrier is leaky. After a time delay of 6-10 h, however, interleukin-1beta messenger RNA is primarily expressed by non-neuronal cells of the brain in the brain parenchyma. These results suggest that the source of initial brain IL-1 activity after peripheral lipopolysaccharide injection derives from cells of the blood-brain barrier and the circumventricular organs, and the sustained interleukin-1 activity in the central nervous system thereafter is derived from glia.

Animals↗

PubMed1999

Temporal and spatial relationships between lipopolysaccharide-induced expression of Fos, interleukin-1beta and inducible nitric oxide synthase in rat brain.

Interleukin-1beta plays an important role in mediating central components of the host response to peripheral infection such as fever and neuroendocrine activation by acting in the brain. The present study assessed whether interleukin-1beta produced in the brain is relevant to neuronal activation and the fever response induced by intraperitoneal injection of bacterial lipopolysaccharide. The distributions of Fos protein, interleukin-1beta protein and inducible nitric oxide synthase messenger RNA, used as an anatomical indicator of interleukin-1beta bioactivity, were compared in brains of animals killed 2, 4 or 8 h after lipopolysaccharide (250 microg/kg) or saline injection. Saline did not induce interleukin-1beta or Fos immunoreactivity in the brain. Interleukin-1beta positive cells were found 2 h after lipopolysaccharide injection in circumventricular organs. Fos immunoreactivity at this time-point was not found in circumventricular organs, but in parenchymal structures such as the nucleus of the solitary tract, paraventricular hypothalamus and ventromedial preoptic area. Fos expression did occur in circumventricular organs only 8 h after lipopolysaccharide injection. This late pattern of Fos expression coincided with the rise in body temperature and the induction of inducible nitric oxide synthase messenger RNA. These data show that after peripheral lipopolysaccharide administration interleukin-1beta is synthesized and bioactive in circumventricular organs. Interleukin-1beta may activate local neurons that induce fever and neuroendocrine activation via projections to the ventromedial preoptic area and the nucleus of the solitary tract.

Abdomen↗

PubMed2003

The effects of acute and chronic lipopolysaccharide infusion in rats on the efferent function of sensory nerves in the isolated mesenteric arterial bed.

Capsaicin-sensitive sensory neurons are stimulated by noxious stimuli, and may be activated in endotoxaemia. The present study investigated the acute and chronic effects of lipopolysaccharide upon the efferent function of these nerves. Conscious rats received infusion (i.v.) of lipopolysaccharide (150 microg kg(-1) h(-1)) or saline for 2 or 24 h. Following infusion, animals were killed and the mesenteric arterial bed isolated and perfused with Krebs' solution. Electrical field stimulation of capsaicin-sensitive sensory nerves was investigated. Postjunctional mechanisms of sensory neurotransmission were examined using calcitonin gene-related peptide, and endothelial and smooth muscle function assessed using acetylcholine and sodium nitroprusside, respectively. All preparations exhibited dose dependency to the agonists, and frequency dependency to electrical field stimulation. No significant differences were observed between the four groups (2-h saline, 24-h saline, 2-h lipopolysaccharide and 24-h lipopolysaccharide) with regard to responses to electrical field stimulation, acetylcholine, sodium nitroprusside or calcitonin gene-related peptide. Thus, the efferent function of capsaicin-sensitive sensory nerves is unaltered in the isolated mesenteric arterial bed prepared ex vivo from rats receiving lipopolysaccharide, either acutely (2 h) or chronically (24 h).

Animals↗

PubMed1994

Lipopolysaccharides of Campylobacter jejuni serotype O:19: structures of core oligosaccharide regions from the serostrain and two bacterial isolates from patients with the Guillain-Barré syndrome.

Lipopolysaccharides from phenol-water extraction of cells of Campylobacter jejuni serotype O:19 were separated into a water-soluble gel of low M(r) and a water-soluble component of high M(r). Acetic acid hydrolysis of the ketosidic linkages to lipid A furnished respectively a core oligosaccharide, the structure of which is reported herein, and an O antigenic polysaccharide. Structural investigations were performed on the O-deacetylated lipopolysaccharide of low M(r), the liberated core oligosaccharide and the various products from removal of neuraminic acid and phosphate residues, and from the Smith degradation. It is concluded that the lipopolysaccharide from the serostrain has a core region with two types of closely related oligosaccharide chains showing striking homologies with gangliosides, the first with a single N-acetylneuraminic acid residue in an outer chain resembling GM1 and the second with two N-acetyl-neuraminic acid residues with a terminal region resembling GD1a. Similar experiments were carried out on lipopolysaccharides of low M(r) from bacterial isolates OH 4384 and OH 4382 serotyped as O:19 that had been obtained from two patients who subsequently developed the Guillain-Barré syndrome. The core oligosaccharide region of lipopolysaccharide from the former isolate differed only slightly from that of the serostrain, whereas that from the latter isolate was distinctly shorter.

Campylobacter jejuni↗

PubMed1991

Structure of the O-specific, sialic acid containing polysaccharide chain and its linkage to the core region in lipopolysaccharide from Hafnia alvei strain 2 as elucidated by chemical methods, gas-liquid chromatography/mass spectrometry, and 1H NMR spectroscopy.

Mild acid hydrolysis of Hafnia alvei strain 2 lipopolysaccharide released no O-specific polysaccharide but instead gave a monomeric octasaccharide repeating unit with N-acetylneuraminic acid as the reducing terminus. In addition, a dimer of the octasaccharide repeating unit, and also a decasaccharide composed of a fragment of the O-specific polysaccharide chain and the core region, were obtained in minute amounts. On the basis of the sugar and methylation analyses, periodate oxidation, and 1H NMR spectroscopy of the lipopolysaccharide hydrolytic products, the biological repeating unit of the O-specific polysaccharide was shown to be a branched octasaccharide: (Formula; see text) The linkage between the O-specific polysaccharide chain and core region has also been determined and has yield strong evidence that N-acetylneuraminic acid is an inherent lipopolysaccharide component. The lipopolysaccharide of H. alvei strain 2 is the first lipopolysaccharide reported to contain 4-substituted neuraminic acid in its O-specific polysaccharide region.

Carbohydrate Conformation↗

PubMed1996

An NMR spectroscopy and molecular mechanics study of the molecular basis for the supramolecular structure of lipopolysaccharides.

Lipopolysaccharides from Gram-negative bacteria interact with the mammalian immune system to trigger a cascade of physiological events leading to a shock syndrome which results in the death in over 70% of cases of severe shock. It is known that the supramolecular structures of lipopolysaccharide aggregates are critical contributors to their biological activities. Despite this, the molecular basis for the formation if the regular hexagonal plates and arrays observed in lipopolysaccharide films and suspensions is unknown. Since these structures are two dimensional, it is unlikely that X-ray crystallographic methods will shed much light on their detailed structure. Knowing this structure is important since it is becoming increasingly likely that the insertion of the lipopolysaccharide hydrocarbon chains in the target host cell membrane may be involved in triggering host responses. This work describes the three-dimensional structure of the lipopolysaccharide lipid A moiety. The structure was obtained by a combination of molecular mechanics calculations and nuclear magnetic resonance spectroscopy. This involved calculation of the dihedral angle between the two glucosamine residues of the lipid A molecule from coupling constants and measuring critical interresidue NOE values. The study also takes into account information from X-ray powder diffraction and electron microscopy studies.

Carbohydrate Conformation↗

PubMed1999

Enhanced interleukin-8 production in THP-1 human monocytic cells by lipopolysaccharide from oral microorganisms and granulocyte-macrophage colony-stimulating factor.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used to assist in bone marrow recovery during cancer chemotherapy. Interleukin-8 (IL-8) plays an important role in macrophage mediated inflammatory processes including exacerbation of periodontal diseases, one of the most common complications in GM-CSF receiving cancer patients. The effect of GM-CSF supplementation on IL-8 production was investigated in a human monocyte cell line THP-1, stimulated with lipopolysaccharide extracted from two oral microorganisms, Porphyromonas gingivalis and Fusobacterium nucleatum. Resting THP-1 cells were treated with lipopolysaccharide (1 microgram/ml) of P. gingivalis or F. nucleatum and/or GM-CSF (50 IU/ml) for varying time periods. The production of IL-8 in THP-1 cells was measured by a solid-phase enzyme-linked immunosorbent assay (ELISA). A very low level of the cytokine IL-8 was produced constitutive in THP-1 cells. Starting from 8 h of treatment and afterwards GM-CSF alone significantly increased IL-8 production in THP-1 cells. Lipopolysaccharide (1 microgram/ml) extracts from either F. nucleatum or P. gingivalis amplified IL-8 production 500-800 times in comparison to resting THP-1 cells. When lipopolysaccharide of F. nucleatum or P. gingivalis was supplemented with 50 IU/ml of GM-CSF, there was a statistically significant enhanced production of IL-8 by THP-1 cells after 1 day to 7 days of treatment as compared with lipopolysaccharide treatment alone. GM-CSF (50 IU/ml) also significantly increased IL-8 production from 2-7 days of treatment of THP-1 cells when supplemented with a positive control, phorbol-12-myristate-13 acetate (PMA), as compared to PMA treatment alone. These investigations using the in vitro THP-1 human monocyte cell model indicate that there may be an increase in the response on a cellular level to oral endotoxin following GM-CSF therapy as evidenced by enhanced production of the tissue-reactive inflammatory cytokine, IL-8.

Cell Line↗

PubMed2003

Depressant effects of ambroxol and erdosteine on cytokine synthesis, granule enzyme release, and free radical production in rat alveolar macrophages activated by lipopolysaccharide.

The present study examined the effects of ambroxol and erdosteine, bronchial expectorants, on the cytokine synthesis, granule enzyme release, and free radical production in rat alveolar macrophages activated by lipopolysaccharide. Ambroxol and erdosteine significantly decreased the production of tumour necrosis factors-alpha, interleukin-1beta, and interleukin-6 in alveolar macrophages activated by lipopolysaccharide. These drugs significantly reduced the production of superoxide anion, hydrogen peroxide, and nitric oxide and the release of acid phosphatase and lysozyme in lipopolysaccharide-activated macrophages. Ambroxol and erdosteine showed no scavenging effect on superoxide anion and hydrogen peroxide, whereas both drugs effectively decomposed nitric oxide. The results show that ambroxol and erdosteine may inhibit the responses, including cytokine synthesis and free radical production, in rat alveolar macrophages activated by lipopolysaccharide. Unlike the production of reactive oxygen species, the inhibitory effect of ambroxol and erdosteine on the production of nitric oxide in lipopolysaccharide-activated alveolar macrophages may be accomplished by a scavenging action on the species and inhibition of the respiratory burst.

Ambroxol↗

PubMed2005

Lipopolysaccharide deacylation by an endogenous lipase controls innate antibody responses to Gram-negative bacteria.

T cell-independent type 1 agonists such as Gram-negative bacterial lipopolysaccharides can stimulate B lymphocytes to proliferate and produce antibodies by signaling through Toll-like receptors. This phenomenon is well established in vitro, yet polyclonal B cell responses after bacterial infection in vivo are often weak and short-lived. We show here that B cell proliferation and polyclonal antibody production in response to Gram-negative bacterial infection are modulated by acyloxyacyl hydrolase, a host enzyme that deacylates bacterial lipopolysaccharides. Deacylation of lipopolysaccharide occurred over several days, allowing lipopolysaccharide to act as an innate immune stimulant yet limiting the eventual amount of B cell proliferation and polyclonal antibody production. Control of lipopolysaccharide activation by acyloxyacyl hydrolase indicates that mammals can regulate immune responses to bacterial infection by chemical modification of a Toll-like receptor agonist.

Acetylation↗