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PubMedDate not supplied

[Characterization of the lipopolysaccharide from the Pseudomonas fluorescens strain IMV 472 (biovar I)].

Lipopolysaccharide was isolated from dry biomass of the Pseudomonas fluorescens strain IMV 472 (biovar I) by the Westphal procedure and purified by ultracentrifugation. Fractions of the structural components of the lipopolysaccharide macromolecule-lipid A, the core oligosaccharide, and the O-chain-were isolated and characterized. 3-Hydroxydecanoic, 2-hydroxydodecanoic, 3-hydroxydodecanoic, hexadecenoic, octadecenoic, and hexadecanoic acids were identified as the main fatty acids of lipid A. The hydrophilic moiety of lipid A was found to include glucosamine, phosphoethanolamine, and phosphate. Glucose, galactose, rhamnose, glucosamine, galactosamine, alanine, phosphoethanolamine, and 2-keto-3-deoxyoctulosonic were identified in the core region of lipid A. The O-specific polysaccharide chain consisted of a repeating tetrasaccharide fragment that included two L-rhamnose residues, a D-fucose residue, and an N-acetyl-D-glucosamine residue as a side substituent. Double immunodiffusion in agar and the lipopolysaccharide precipitation reaction revealed no serological interrelation between strain IMV 472 and P. fluorescens strains studied previously.

Carbohydrate Conformation↗

PubMed1996

Bacterial lipopolysaccharide induces diarrhoea in caecectomized mice.

Castor oil, lipopolysaccharide of Escherichia coli, and endotoxin of Salmonella typhimurium were used for inducing diarrhoea in sham operated or caecectomized mice. Copious diarrhoea was induced by lipopolysaccharide (LPS) in caecectomized mice. Characteristics of diarrhoea induced by castor oil were not different between the two groups. It is concluded that caecectomized mice may be a good model to study lipopolysaccharide-induced diarrhoea.

Animals↗

PubMed1997

(-)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-kappaB.

Nitric oxide (NO) plays an important role in inflammation and multiple stages of carcinogenesis. We investigated the effect of various tea polyphenols and caffeine on the induction of NO synthase (NOS) in thioglycollate-elicited and lipopolysaccharide (LPS)-activated peritoneal macrophages. Gallic acid (GA), (-)-epigallocatechin (EGC), and (-)-epigallocatechin-3-gallate (EGCG), the major tea catechin, were found to inhibit inducible NOS (iNOS) protein in activated macrophages. EGCG, a potent antitumor agent with anti-inflammatory and antioxidant properties, inhibited NO generation, as measured by the amount of nitrite released into the culture medium. Inhibition of NO production was observed when cells were cotreated with EGCG and LPS. iNOS activity in soluble extracts of lipopolysaccharide-activated macrophages treated with EGCG (5 and 10 microM) for 6-24 hr was significantly lower than that in macrophages without EGCG treatment. Western blot, reverse transcription-polymerase chain reaction, and Northern blot analyses demonstrated that significantly reduced 130-kDa protein and 4.5-kb mRNA levels of iNOS were expressed in lipopolysaccharide-activated macrophages with EGCG compared with those without EGCG. Electrophoretic mobility shift assay indicated that EGCG blocked the activation of nuclear factor-kappaB, a transcription factor necessary for iNOS induction. EGCG also blocked disappearance of inhibitor kappaB from cytosolic fraction. These results suggest that EGCG decreases the activity and protein levels of iNOS by reducing the expression of iNOS mRNA and the reduction could occur through prevention of the binding of nuclear factor-kappaB to the iNOS promoter, thereby inhibiting the induction of iNOS transcription.

Animals↗

PubMed1997

Interleukin-1 response to arterial antigen, lipopolysaccharide, and oxidized low density lipoprotein in ischemic heart disease.

UNLABELLED: Monocytes responding to oxidized low density lipoprotein (LDL) or other antigens may initiate atherogenesis through production of interleukin-1 (IL-1) and additional cytokines. Interleukin-1 is chemotactic for circulating leukocytes, can stimulate growth of fibroblasts or smooth muscle cells, and causes activation of T- and B-lymphocytes. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 42 patients with angiographically verified ischemic heart disease (IHD) and 35 age-matched control subjects without a history of cardiac disease. Rates of proliferation and production of IL-1 beta were measured after peripheral blood mononuclear cells were cultured for 7 days in the presence of mitogens, arterial antigen, lipopolysaccharide, or native and oxidized forms of LDL. RESULTS: In patients with IHD, proliferation in response to arterial antigen was either diminished or unchanged from control values. Peripheral blood mononuclear cells from IHD and control patients had similar levels of proliferation after treatment with different mitogens. Levels of IL-1 beta, produced after stimulation with arterial antigen or lipopolysaccharide, also did not differ for PBMCs obtained from control and IHD patients. For patients with either a stable angina pattern or no history of cardiac disease, PBMC cultured in the presence of native and oxidized forms of LDL released similar amounts of IL-1 beta. In contrast, PBMCs from 4 patients with unstable angina had increased levels of IL-1 beta after culture in the presence of oxidized LDL (group means +/- standard deviation of 1.63 +/- 1.08 pg/mL for 17 control patients, 0.96 +/- 0.23 pg/mL for 4 cases with stable angina, and 4.02 +/- 5.91 pg/mL, for 19 cases with unstable angina). These values reflect a greater than 5-fold increase in variability for IL-1 beta produced on exposure to oxidized LDL for patients with unstable angina relative to control patients. CONCLUSIONS: Effects of in vitro stimulation with mitogens or lipopolysaccharide are similar for PBMC obtained from normal or IHD patients. The response to arterial antigen is also not increased in cells from patients with IHD. However, PBMCs obtained from a subset of patients with unstable angina produce greater levels of IL-1 beta after treatment with oxidized, but not native, LDL.

Adult↗

PubMed1997

Role of peroxynitrite in the protein oxidation and apoptotic DNA fragmentation in vascular smooth muscle cells stimulated with bacterial lipopolysaccharide and interferon-gamma.

In the present study, we investigated the role of endogenous and exogenous peroxynitrite in the process of DNA fragmentation and protein oxidation in cultured rat aortic smooth muscle cells. Peroxynitrite induced DNA fragmentation over a 24 hr period. The effect of peroxynitrite was unaffected by pretreatment with 3-aminobenzamide, an inhibitor of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Stimulation of the smooth muscle cells with bacterial lipopolysaccharide and interferon-gamma produced nitric oxide and peroxynitrite, and resulted in a significant degree of apoptotic DNA fragmentation. The nitric oxide synthase inhibitor NG-methyl-L-arginine (3 mM), but not the PARS inhibitor 3-aminobenzamide (1 mM), reduced the DNA fragmentation. Stimulation with bacterial lipopolysaccharide and interferon-gamma also caused a marked oxidation of proteins in the smooth muscle cells, which was inhibited by NG-methyl-L-arginine, as well as by the superoxide dismutase mimetic Mn(III)tetrakis (4-benzoic acid) porphyrin. Based on these data, we propose a role for peroxynitrite-mediated, PARS-independent pathways in the apoptotic process and in the protein oxidation in bacterial lipopolysaccharide and interferon-gamma-stimulated smooth muscle cells.

Animals↗

PubMed1976

Genetic differences between endotoxin-sensitive and resistant C3H mice. Intraperitoneal cell response to lipopolysaccharide and prostaglandins.

The 2 related mouse strains C3H/HeJ and C3/Han differe in their response to endotoxin. C3H/HeJ mice are endotoxin-resistant, C3H/Han mice are - like all other mice - endotoxin-sesinsitive. The uptake of fluorescent intraperitoneally injected lipopolysaccharide was similar in both mouse strains. The intraperitoneal injection of lipopolysaccharide produced a higher mobilization of neutrophil granulocytes in resistant C3H/HeJ mice than in C3H/Han mice. An opposite pattern of mobilization of neutrophil granulocytes could be observed after injection of the prostaglandins E 1, E 2, and F 1 alpha: which both mouse strains were compared, a normal mobilization was observed in C3H/Han mice. C3H/HeJ mice showed a markedly decreased mobilization. If the difference between the 2 strains resides in a single gene locus itis to be assumed that lipopolysaccharide resistance is controlled by the same gene which also effects an impaired response to neutrophil mobilization after prostaglandin application.

Animals↗

PubMed1999

Lipopolysaccharide injected into the cerebral ventricle evokes fever through induction of cyclooxygenase-2 in brain endothelial cells.

Activation of the arachidonic acid cascade is an essential step for the development of fever during brain inflammation. We investigated the brain sites where this activation takes place by use of a rat model of brain inflammation. Intracerebroventricular administration of lipopolysaccharide but not of its vehicle evoked fever. The fever was markedly suppressed when the rats had been pretreated with a cyclooxygenase-2-specific inhibitor. In situ hybridization and immunohistochemical studies revealed that cyclooxygenase-2 mRNA and its protein were induced by lipopolysaccharide in blood vessels near the cerebral ventricles and in those in the subarachnoidal space. Double immunohistochemical staining revealed that these cyclooxygenase-2-positive cells were mostly endothelial cells. The time course of fever and that of cyclooxygenase-2 induction in the endothelial cells were in parallel. Cyclooxygenase-2 mRNA in a certain type of telencephalic neurons was also upregulated by the intracerebroventricular administration, but this neuronal response occurred both in vehicle-injected rats and in lipopolysaccharide-injected ones to the same extent. Therefore, the neuronal response was not essential to the development of fever. These results suggest that brain endothelial cells play a crucial role in the development of fever during brain inflammation by activating their arachidonic acid cascade.

Animals↗

PubMed2005

Lipopolysaccharide recognition protein, MD-2, facilitates cellular uptake of E. coli-derived plasmid DNA in synovium.

BACKGROUND: Several cell types are susceptible to transfection in vivo using naked plasmid DNA. The mechanisms involved in mediating in vivo transfection are incompletely known, but evidence suggests that receptor-mediated endocytosis is important for specific types of cells. In this study we tested the hypothesis that residual Escherichia coli lipopolysaccharide (LPS) forms a non-covalent complex with expression plasmid DNA, and host-cell-derived soluble LPS-binding proteins bind to the DNA-LPS complexes in order to facilitate receptor-mediated endocytosis. METHODS: Cells from the murine synovial lining were used as an in vivo model system and in vivo luciferase imaging was used to quantify levels of transgene expression. Using a series of gene-deleted mice, the roles of LPS recognition complex proteins, lipopolysaccharide-binding protein (LBP), CD14 and MD-2, in the process of in vivo transfection were determined. RESULTS: Luciferase expression assays revealed that mice lacking LBP or CD14 had increased luciferase expression (p < 0.023 and < 0.165, respectively), while mice deleted of MD-2 had significant reductions in luciferase expression (p < 0.001). Gene deletion of hyaluronic acid binding protein CD44 was used as a control and had no statistically significant effect on transgene expression in vivo. In muscle tissue, where neither cell surface nor soluble MD-2 is expressed, no MD-2 dependence of plasmid transfection was identified, suggesting the role of MD-2 is tissue or cell type specific. Additionally, depleting mice of macrophages showed that luciferase expression is occurring within fibroblast-like synoviocytes. CONCLUSIONS: Our data support a physical association between LPS and E. coli-derived plasmid DNA, and that in vivo transfection of fibroblast-like synoviocytes is dependent on the soluble form of the LPS-binding protein MD-2.

Acute-Phase Proteins↗

PubMed1995

Characterisation of bovine lipopolysaccharide binding protein and the in vivo acute phase response to Pasteurella haemolytica Type A.

Lipopolysaccharide binding protein (LBP) is a liver-derived acute phase protein which is implicated in modulating the host responses to lipopolysaccharide (LPS) from Gram-negative bacteria. LBP interacts with circulatory LPS to form complexes which bind to the CD14 receptor or cells of the monocytic lineage and neutrophils resulting in their activation. This causes the release of mediators and cytokines which are responsible for initiating the acute phase response. LBP-like activity has now been identified in bovine serum and in this study LBP has been purified from acute phase bovine serum using ion exchange chromatography. On sodium dodecyl sulphate polyacrylamide electrophoresis, bovine LBP demonstrated a single band with a molecular mass of 58 kDa. Bovine LBP enhanced the binding of LPS to human monocytes while enzymatic removal of the CD14 receptor abrogated this interaction. Furthermore, bovine LBP increased the sensitivity of monocytes to LPS by at least 100-fold. Depletion of LBP by means of antibodies to bovine LBP inhibited the serum mediated LPS binding to monocytes. Antibodies to rabbit LBP or recombinant human LBP did not cross-react with bovine LBP. Studies on the kinetics of LBP activity in calves during the acute phase response demonstrated a four-fold increase in the serum concentration 36 h after a single intratracheal inoculation of Pasteurella haemolytica A1. The findings of this study indicate that cattle possess a LPS detection mechanism comparable to that described in man and experimental animals in which LBP forms complexes in serum with circulatory LPS enhancing the signal to the immune system to mount a host response. The isolation of LBP will allow further investigations into LBP-mediated responses to LPS in cattle.

Acute-Phase Proteins↗

PubMed2004

Polymorphisms of the lipopolysaccharide-signaling complex in inflammatory bowel disease: association of a mutation in the Toll-like receptor 4 gene with ulcerative colitis.

Genes encoding for receptors of the innate immune system are potential candidates for susceptibility to inflammatory bowel disease, e.g., mutations in the cytosolic receptor NOD2/CARD15 were associated with Crohn's disease. Herein, two mutations of the Toll-like receptor (TLR)-4 gene (Asp299Gly and Thr399Ile) resulting in impaired lipopolysaccharide signaling, the -159C/T promotor polymorphism of the CD14 gene, polymorphisms of the lipopolysaccharide binding protein gene and the bactericidal permeability increasing protein gene were evaluated in 102 patients with Crohn's disease, 98 patients with ulcerative colitis and 145 healthy controls. The allele and carrier frequencies for the Thr399Ile mutation in TLR4 gene were significantly increased in ulcerative colitis when compared to the controls (P = 0.014 and P = 0.018, respectively). None of the other five polymorphisms was associated with inflammatory bowel disease. In conclusion, a novel association between a functional polymorphism in TLR4 and ulcerative colitis is reported. This observation underscores the importance of impaired innate immunity in inflammatory bowel disease.

Acute-Phase Proteins↗

PubMed1997

Lipopolysaccharide-binding protein is required to combat a murine gram-negative bacterial infection.

An invading pathogen must be held in check by the innate immune system until a specific immune response can be mounted. In the case of Gram-negative bacteria, the principal stimulator of the innate immune system is lipopolysaccharide (LPS), a component of the bacterial outer membrane. In vitro, LPS is bound by lipopolysaccharide-binding protein (LBP) and transferred to CD14--the LPS receptor on the macrophage surface--or to high-density lipoprotein (HDL) particles. Transfer to CD14 triggers an inflammatory response which is crucial for keeping an infection under control. Here we investigate how LBP functions in vivo by using LBP-deficient mice. Surprisingly, we find that LBP is not required in vivo for the clearance of LPS from the circulation, but is essential for the rapid induction of an inflammatory response by small amounts of LPS or Gram-negative bacteria and for survival of an intraperitoneal Salmonella infection.

Acute-Phase Proteins↗

PubMed1998

Lipopolysaccharide pretreatment produces macrophage endotoxin tolerance via a serum-independent pathway.

BACKGROUND: Lipopolysaccharide activation (LPSa) of macrophages is thought to occur via a CD14-dependent mechanism with a requirement for the serum factor, lipopolysaccharide binding protein. LPS-stimulated, CD14-dependent signal transduction is associated with phosphorylation of mitogen-activated protein kinase (MAPK), nuclear factor-kappaB (NF-kappaB) translocation, and secretion of tumor necrosis factor (TNF) and interleukin-1 (IL-1). Macrophage endotoxin tolerance after low-dose LPS pretreatment (LPSp) is characterized by inhibition of LPSa-stimulated TNF and augmentation of IL-1 secretion. We sought to determine the role of CD14-dependent pathways in the induction of endotoxin tolerance by comparing the effects of LPSp in the presence or absence of serum. METHODS: Murine peritoneal macrophages were exposed to a range of LPSp concentrations in the presence or absence of serum. MAPK activation and NF-kappaB were assayed 30 minutes after LPSp stimulation. TNF production and IL-1 were measured 6 hours after stimulation with 100 ng/mL LPSa, with or without 24-hour 10 ng/mL LPSp. RESULTS: In the presence of serum, 100 ng/mL LPSp activated MAPK and NF-kappaB, whereas no activation of MAPK or NF-kappaB was seen at this LPSp concentration in the absence of serum. The absence of serum during 10 ng/mL LPSp did not prevent LPSp-mediated inhibition of TNF secretion, and it significantly augmented IL-1 secretion after stimulation with 100 ng/mL LPSa in the presence of serum. CONCLUSION: Induction of the alterations in subsequent LPSa-stimulated cytokine secretion characteristic of endotoxin tolerance by LPSp occurs via a serum-independent signal transduction pathway.

Acute-Phase Proteins↗

PubMed2006

Upregulation of TNF-alpha and IL-6 mRNA in mouse liver induced by bacille Calmette-Guerin plus lipopolysaccharide.

AIM: To investigate the mechanism of immunological liver injury induced by bacille Calmette-Guerin (BCG) plus lipopolysaccharide (LPS). METHODS: Mice were injected via the tail vein with 125 mg/kg BCG, and 12 d later, the mice were injected intravenously with different doses of LPS (125, 250, or 375 microg/kg). Serum alanine aminotransferase (ALT) activity and liver pathological changes were examined. The expression of tumor necrosis factor (TNF)- alpha, interleukin (IL)-6, lipopolysaccharide binding protein (LBP) and CD14 mRNA, and NF-kappaB and IkappaB-alpha protein in mouse liver at different time points after BCG and LPS injection were measured using RT-PCR, immunohistochemistry and Western blotting analysis, respectively. RESULTS: The activity of serum ALT in mice treated with BCG and LPS was significantly increased. Different degrees of liver injury, such as inflammatory cell infiltration, spotty necrosis, piecemeal necrosis, even bridging necrosis, could be seen in liver sections from mice after BCG and LPS administration. Furthermore, the levels of TNF-alpha and IL-6 mRNA in mouse liver were significantly elevated after administration of BCG plus LPS (P<0.05). The levels of LBP and CD14 mRNA in mouse liver were markedly upregulated after treatment with BCG and LPS, and treatment with BCG alone led to an increase in CD14 mRNA in mouse liver. Finally, immunoreactivity for NF-kappaB p65 was predominantly detected in hepatocyte nuclei from mice treated with BCG plus LPS, compared with the normal group. Protein levels of IkappaB-alpha were strikingly decreased by LPS or BCG plus LPS treatment, compared with the normal group or BCG group. CONCLUSION: TNF-alpha and IL-6 mRNA were partially involved in early immunological liver injury induced by challenge with small doses of LPS after BCG priming. Upregulation of TNF-alpha and IL-6 mRNA might be related to increases in LBP and CD14 mRNA expression and activation of NF-kappaB. Furthermore, BCG priming in immunological liver injury may occur via upregulation of CD14 mRNA expression in mononuclear cell infiltration into the liver.

Acute-Phase Proteins↗

PubMed1990

CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein.

Leukocytes respond to lipopolysaccharide (LPS) at nanogram per milliliter concentrations with secretion of cytokines such as tumor necrosis factor-alpha (TNF-alpha). Excess secretion of TNF-alpha causes endotoxic shock, an often fatal complication of infection. LPS in the bloodstream rapidly binds to the serum protein, lipopolysaccharide binding protein (LBP), and cellular responses to physiological levels of LPS are dependent on LBP. CD14, a differentiation antigen of monocytes, was found to bind complexes of LPS and LBP, and blockade of CD14 with monoclonal antibodies prevented synthesis of TNF-alpha by whole blood incubated with LPS. Thus, LPS may induce responses by interacting with a soluble binding protein in serum that then binds the cell surface protein CD14.

Acute-Phase Proteins↗

PubMed2005

Inhibition of lipopolysaccharide-induced inflammatory responses by an apolipoprotein AI mimetic peptide.

Previous studies suggest that high-density lipoprotein and apoAI inhibit lipopolysaccharide (LPS)-induced inflammatory responses. The goal of the current study was to test the hypothesis that the apoAI mimetic peptide L-4F exerts antiinflammatory effects similar to apoAI. Pretreatment of human umbilical vein endothelial cells (HUVECs) with LPS induced the adhesion of THP-1 monocytes. Incubation of cells with LPS and L-4F (1 to 50 microg/mL) reduced THP-1 adhesion in a concentration-dependent manner. This response was associated with a significant reduction in the synthesis of cytokines, chemokines, and adhesion molecules. L-4F reduced vascular cell adhesion molecule-1 expression induced by LPS or lipid A, whereas a control peptide (Sc-4F) showed no effect. In contrast to LPS treatment, L-4F did not inhibit IL-1beta- or tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression. The inhibitory effect of L-4F on LPS induction of inflammatory markers was associated with reduced binding of LPS to its plasma carrier molecule, lipopolysaccharide binding protein, and decreased binding of LPS to HUVEC monolayers. LPS and L-4F in HUVEC culture medium were fractionated by fast protein liquid chromatography and were localized to the same fractions, suggesting a physical interaction between these molecules. Proinflammatory responses to LPS are associated with the binding of lipid A to cell surface receptors. The current studies demonstrate that L-4F reduces the expression of inflammatory markers induced by LPS and lipid A and suggest that apoAI peptide mimetics may be useful in the treatment of inflammation associated with endotoxemia.

Acute-Phase Proteins↗

PubMed1997

Release of lipopolysaccharide toxicity-modulating proteins in patients undergoing cardiopulmonary bypass using noncoated and heparin-coated extracorporeal circuits. A clinical pilot study.

STUDY OBJECTIVE: Cardiopulmonary bypass (CPB) induces a generalized inflammatory response, including activation of leukocytes, contributing to postoperative morbidity. The inflammatory pathways leading to this systemic inflammatory response syndrome are considered identical to those involved in septic shock. Therefore, we studied the release of bactericidal/permeability-increasing protein (BPI), lipopolysaccharide binding protein (LBP), and soluble CD14 (sCD14)-all proteins that modulate the effects of lipopolysaccharide (LPS)-in patients undergoing CPB. In addition, the effect of heparin coating of the extracorporeal bypass circuit on the release of these parameters was assessed. DESIGN: Prospective, randomized clinical pilot study. SETTING: Cardiothoracic Surgery Department in a university hospital. PATIENTS: Fourteen patients undergoing elective coronary artery bypass grafting were included. Seven patients underwent CPB using a standard, noncoated extracorporeal circuit, and seven patients had CPB using a heparin-coated extracorporeal circuit (Duraflo II). INTERVENTIONS: Blood samples were taken after induction of anesthesia, just before aortic crossclamping, and 0, 0.5, 1.5, 3, 6, 12, and 24 h after declamping. MEASUREMENTS AND RESULTS: CPB with a noncoated extracorporeal circuit induced a sharp increase in neutrophil-derived BPI, manifest directly after release of the aortic crossclamp, which was significantly attenuated using a heparin-coated system. Also, CPB induced a gradual increase of the acute-phase reactant LBP, which was identical in the noncoated and heparin-coated groups. Systemic release of sCD14 after crossclamp release was significantly higher in the noncoated group compared with the heparin-coated group, but did not rise above baseline levels. CONCLUSIONS: These data confirm that CPB-induced leukocyte activation is attenuated using a heparin-treated extracorporeal circuit and point to the possible role of LPS toxicity-modulating proteins in the systemic inflammatory response after bypass surgery.

Acute-Phase Proteins↗

PubMed1994

Monocyte tissue factor induction by lipopolysaccharide (LPS): dependence on LPS-binding protein and CD14, and inhibition by a recombinant fragment of bactericidal/permeability-increasing protein.

Mononuclear phagocytes, stimulated by bacterial lipopolysaccharide (LPS), have been implicated in the activation of coagulation in sepsis and endotoxemia. In monocytes LPS induces the synthesis of tissue factor (TF) which, assembled with factor VII, initiates the blood coagulation cascades. In this study we investigated the mechanism of LPS recognition by monocytes, and the consequent expression of TF mRNA and TF activity. We also studied the inhibition of these effects of LPS by rBPI23, a 23-kD recombinant fragment of bactericidal/permeability increasing protein, which has been shown to antagonize LPS in vitro and in vivo. Human peripheral blood mononuclear cells, or monocytes isolated by adherence, were stimulated with Escherichia coli O113 LPS at physiologically relevant concentrations (> or = 10 pg/mL). The effect of LPS was dependent on the presence of the serum protein LBP (lipopolysaccharide-binding protein), as shown by the potentiating effect of human recombinant LBP or serum. Furthermore, recognition of low amounts of LPS by monocytes was also dependent on CD14 receptors, because monoclonal antibodies against CD14 greatly reduced the LPS sensitivity of monocytes in the presence of serum or rLBP. Induction of TF activity and mRNA expression by LPS were inhibited by rBPI23. The expression of tumor necrosis factor showed qualitatively similar changes. Considering the involvement of LPS-induced TF in the potentially lethal intravascular coagulation in sepsis, inhibition of TF induction by rBPI23 may be of therapeutic benefit.

Acute-Phase Proteins↗

PubMed2000

Up-regulation of endothelin-converting enzyme-1 in gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide.

Endothelin-1 (ET-1) is a vasoactive peptide produced from a biologically inactive big ET-1 by the action of endothelin-converting enzyme-1 (ECE-1). We investigated gastric mucosal expression of ECE-1 during a 10-day course of inflammatory responses associated with acute gastritis elicited by Helicobacter pylori lipopolysaccharide. The ECE-1 activity was associated with microsomal fraction and the level of its expression reflected the extent of mucosal inflammatory involvement. The histologic pattern of inflammation reached a maximum on the 4th day following the lipopolysaccharide and was accompanied by a 4.1-fold enhancement in the expression of ECE-1 activity and a significant elevation in ET-1 (3.1-fold), TNF-alpha (8.8-fold), and apoptosis (11.6-fold). A 41.5% decrease in the severity of mucosal inflammation by the 10th day following the lipopolysaccharide was reflected in a 62.3% reduction in the mucosal expression of ECE-1 and a decline in TNF-alpha, ET-1, and apoptosis. Thus, H. pylori infection causes up-regulation of gastric mucosal ECE-1 expression, which leads to the enhancement of ET-1 production, induction of TNF-alpha, and triggering the apoptotic events that exacerbate the inflammatory process.

Animals↗