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 intracellular serine protease zymogen, factor C, is an initiator in the hemolymph coagulation system of horseshoe crab. We purified this zymogen from the hemocytes of the American horseshoe crab, Limulus (L.) polyphemus, the objective being to compare its properties with those of the Japanese horseshoe crab, Tachypleus (T.) tridentatus, factor C. The purified zymogen L.-factor C showed similar properties to those of T.-factor C, in terms of molecular mass (123,000), amino acid composition (1,011 residues), subunit structure (two chains), and antigenicity. Like the zymogen T.-factor C, this zymogen was also activated autocatalytically in the presence of bacterial lipopolysaccharide (LPS) and its synthetic lipid A analogue. A most interesting finding is that both protease zymogens are rapidly activated by alpha-chymotrypsin or rat mast cell chymase, but not by trypsin. The active enzyme factor C showed alpha-thrombin-like specificity toward synthetic tripeptide substrates. This factor C was also strongly inhibited by an alpha-thrombin inhibitor, D-Phe-Pro-Arg-chloromethyl ketone. Thus, the enzymatic properties of factor C are similar to those of mammalian alpha-thrombin. On the other hand, the coagulation cascade system present in the hemocyte lysate was activated when chymotrypsin, free from LPS, was added to the lysate used to detect the endotoxins. The implication of our findings is that the chymotrypsin-catalyzed initiation of the horseshoe crab coagulation system is unique, since all known mammalian coagulation, fibrinolysis and complement systems are initiated by trypsin-like enzymes.
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PMID:Further studies on lipopolysaccharide-sensitive serine protease zymogen (factor C): its isolation from Limulus polyphemus hemocytes and identification as an intracellular zymogen activated by alpha-chymotrypsin, not by trypsin. 201 64

Exposure to lipopolysaccharide (LPS) primes polymorphonuclear leucocytes (PMNL) for enhanced release of oxygen metabolites after subsequent stimulation. The metabolic response of human PMNL primed with LPS and stimulated with formyl-methionyl-leucyl-phenylalanine (FMLP) was measured by chemiluminescence (CL) as a parameter for endotoxic activity. Polymyxin B (PMB) and monoclonal antibodies (MAbs) with specificity for lipid A were tested for inhibition of the priming effect of Re LPS of Salmonella minnesota R595, Rc LPS of Escherichia coli J5 and smooth LPS of E. coli O111. The CL response of PMNL primed with Re LPS or Rc LPS was higher than that of PMNL primed with smooth LPS. Pre-incubation of rough or smooth LPS with PMB caused dose-dependent inhibition of priming of PMNL. Two IgM MAbs, 8-2 and 26-20, which recognise different epitopes on the hydrophobic part of lipid A, also completely prevented priming of PMNL by either rough or smooth LPS. The dose-dependent inhibitory effect of both MAbs was similar to the inhibition by PMB. These results indicate that the binding of MAbs to the hydrophobic part of lipid A is important in blocking lipid A-mediated effects.
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PMID:Inhibition by lipid A-specific monoclonal antibodies of priming of human polymorphonuclear leucocytes by endotoxin. 202 18

Gram-negative bacterial sepsis is frequently associated with acute renal failure but the specific effects of lipopolysaccharide (LPS) and other bacterial products on kidney function are not known. Since either LPS or formyl-methionyl-leucyl-phenylalanine (FMLP)--a chemotactic peptide from bacterial cell walls--activate neutrophils (PMN) to release a number of potentially toxic factors in vitro, we determined the effect of adding PMN with LPS and/or FMLP to isolated perfused rat kidneys. Isolated rat kidneys perfused with LPS alone or LPS and normal PMN had normal glomerular filtration rates (GFR) and tubular Na reabsorption (TNa). Kidneys perfused with FMLP alone or FMLP and normal PMN also had normal GFR and TNa. In contrast, addition of PMN with both FMLP and LPS caused progressive renal dysfunction. For example, after 60 minutes of perfusion, GFR was reduced from 610 +/- 31 to 147 +/- 17 microliters/min/g and TNa from 97 +/- 1 to 72 +/- 2%, both P less than 0.01. Perfusion with the O2 metabolite scavengers catalase or dimethylthiourea afforded no protection while perfusion with the neutrophil elastase inhibitor Eglin C conferred substantial, but not complete, protection: GFR 492 +/- 34 microliters/min/g; TNa 91 +/- 3%. However, perfusion with both Eglin C and catalase completely prevented the toxic effects of LPS and FMLP-treated PMN on renal function. We conclude that in isolated kidneys, 1) the toxic effects of LPS requires FMLP-treated PMN and that 2) LPS and FMLP treated PMN cause progressive renal injury which is mediated by both O2 metabolites and neutrophil elastase.
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PMID:Role of neutrophil derived oxidants and elastase in lipopolysaccharide-mediated renal injury. 205 18

Peripheral blood-derived human polymorphonuclear leukocytes (PMNL) can be induced to synthesize prostaglandin E2 (PGE2) from endogenous and exogenous arachidonic acid (AA) when exposed to agents such as human recombinant (hr) granulocyte-macrophage (GM) colony-stimulating factor (CSF), hr tumor necrosis factor-alpha, hr granulocyte (G)-CSF, lipopolysaccharide and the chemoattractant N-formyl-methionyl-leucyl-phenylalanine. Treatment of PMNL with hr macrophage (M)-CSF and interleukin 3, however, did not result in detectable PGE2 synthesis. Cytokines stimulated PGE2 production during two distinct time intervals, an early peak of PGE2 that was detectable at 20 min and a late one detectable after 4 h. Inhibition of protein synthesis by cycloheximide (CHX) had virtually no effect on the early increase of PGE2 but prevented the late increase. Late addition of CHX to cultures after stimulation with hr GM-CSF at 4 h resulted in decline of PGE2 synthesis from exogenous arachidonic acid. Treatment of PMNL with GM-CSF had direct effects on cyclooxygenase (COx). PMNL depleted from COx by acetyl salicylic acid (ASA) recovered to synthesize PGE2 following exposure to GM-CSF. Recovery from COx inhibition by ASA could be prevented by CHX.
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PMID:Cytokine-stimulation of prostaglandin synthesis from endogenous and exogenous arachidonic acids in polymorphonuclear leukocytes involving activation and new synthesis of cyclooxygenase. 212 94

Pseudomonas aeruginosa elastase is a zinc metalloproteinase which is released during P. aeruginosa infections. Pseudomonas keratitis, which occurs following contact lens-induced corneal trauma, can lead to rapid, liquefactive necrosis of the cornea. This destruction has been attributed to the release of both host-derived enzymes and the bacterial products P. aeruginosa elastase, alkaline protease, exotoxin A, and lipopolysaccharide endotoxin. A synthetic metalloproteinase inhibitor, HSCH2 (DL)CH[CH2CH(CH3)2]CO-Phe-Ala-NH2, which we previously showed to be a potent inhibitor of corneal collagenase and alkali-induced corneal ulceration, was tested as a potential inhibitor of P. aeruginosa elastase. Inhibition constants (Kis) for the resolved diastereomers were determined with the chromogenic substrate furylacryloyl-glycyl-L-leucyl-L-alanine. One isomer had a Ki of 0.3 microM, while the other had a Ki of 0.4 microM. The more potent diastereomer was evaluated in vivo in experimentally induced Pseudomonas keratitis in rabbits. Following inoculation of one cornea of each rabbit, topical treatment with a 1 mM solution of the inhibitor significantly delayed the onset of corneal melting and perforation, as compared with the results for the control and gentamicin-treated groups. This protective effect suggests that the inhibitor may have a therapeutic application by delaying the progression of corneal destruction in Pseudomonas keratitis.
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PMID:Inhibition of Pseudomonas aeruginosa elastase and Pseudomonas keratitis using a thiol-based peptide. 212 41

Human periodontal ligament-derived fibroblasts (HPLF) were grown to confluency in culture and were subjected to various combinations of neutrophils (PMNs), lipopolysaccharide (LPS) and the chemoattractant formylmethionyl-leucyl-phenylalanine (FMLP). After treatment, the cells were stained to distinguish between normal and damaged cells. The stain also allowed an estimation of PMN adherence to the HPLF monolayer. We report that FMLP, LPS or PMNs alone did not damage HPLF cells, nor did PMNs when combined with LPS or FMLP separately. However, PMNs subjected to combinations of LPS (10-1000 ng/ml) and FMLP (10(-9)-10(-6) M) caused significant PMN-mediated fibroblast damage. LPS concentrations greater than 1000 ng/ml inhibited the cytotoxic reaction. Furthermore, we found that FMLP alone did not significantly enhance PMN adherence to the HPLF monolayer but that LPS increased PMN adherence 3-fold and the combination of LPS and FMLP enhanced adherence 6-fold. We conclude that LPS promotes PMN adherence to fibroblasts and that such adherence appears to be a crucial, but insufficient stimulus, for the induction of PMN-mediated HPLF injury.
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PMID:Neutrophil-mediated damage to human periodontal ligament-derived fibroblasts: role of lipopolysaccharide. 214 14

Human peripheral blood neutrophils are primed, or enabled to respond to formyl peptide, by prior exposure to bacterial lipopolysaccharide (LPS). The activity of LPS and the size of its aggregates are altered by plasma constituents such as high density lipoprotein (HDL) and the recently discovered acute phase reactant lipopolysaccharide binding protein (LBP) Tobias et al.: J. Exp. Med. 164,777, 1986]. The ability of LPS, LPS-LBP, and LPS-HDL complexes to activate a number of cellular responses have been compared. LPS-LBP and LPS-HDL were prepared using LBP and HDL from rabbit serum. LPS from Salmonella minnesota Re595 and its LPS-LBP and LPS-HDL complexes differed in their ability to prime PMN O2- production in response to formyl peptide (f-Nle-Leu-Phe-Nle-Tyr-Leu [FNLPNTL]). Human PMN prepared under conditions in which O2- production is minimal (less than 1 nmol O2-/10(6) PMN/10 min) after exposure to 10(-7) M FNLPNTL can be primed with 0.1-100 ng/ml LPS in a dose- and time-dependent manner to produce up to 12 nmol O2-/10(6) PMN/10 min. LBP complexation accelerated the priming induced by LPS, whereas HDL complexation retarded it. Priming was accompanied by a parallel two- to threefold increase in formyl peptide receptor number as determined by FACS analysis of fluoresceinated FNLPNTL binding and SDS-PAGE autoradiographic analysis of photoaffinity ligand binding. Thus binding of LPS to plasma proteins changes the response of the PMS to LPS and may represent one way in which the response of the PMN is regulated during infection. Since LBP concentrations change during an acute phase response, complexation of LPS with LBP is a mechanism that may regulate neutrophil responses in vivo during inflammation.
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PMID:Priming of polymorphonuclear granulocytes by lipopolysaccharides and its complexes with lipopolysaccharide binding protein and high density lipoprotein. 215 25

The mechanism(s) involved in the generation of free radicals in human leukocytes by phorbol myristate acetate (PMA), formyl-methionyl-leucyl-phenylalanine (FMP), lipopolysaccharide (LPS), arachidonic acid (AA), and recombinant-tumor necrosis factor-1-alpha (r-TNF-1 alpha) was investigated. Calmodulin antagonists, chlorpromazine and trifluoperazine, inhibited free radical generation in human leukocytes by these stimulants. Dexamethosone, an inhibitor of phospholipase A2, could also block free radical generation in human leukocytes induced by r-TNF 1 alpha. PMA, FMP, LPS and TNF can activate phospholipase A2 and induce the release of AA from the cell membrane lipid pool. AA induced free radical generation in human leukocytes can be inhibited by calmodulin antagonists. Hence, it is likely that calmodulin dependent events play a crucial role in the generation of free radicals by human leukocytes in response to various stimulants including TNF.
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PMID:Stimulation of free radical generation in human leukocytes by various agents including tumor necrosis factor is a calmodulin dependent process. 215 20

Human neutrophils were primed by exudation or pretreatment with a synthetic diacylglycerol (diC10), the Ca2+ ionophore ionomycin or lipopolysaccharide (LPS). Compared to control cells, these primed cells showed a significantly decreased O2-/H2O2 ratio when stimulated with formylmethionyl-leucyl-phenylalanine (FMLP). This shift indicates a comparative (and net) increased H2O2 detection in the extracellular medium and can not be explained by a dose-dependent impairment in either O2- or H2O2 detecting capacity. An altered H2O2 degenerating capacity was not observed in the primed cells. We propose that priming enhances the capacity to divalently reduce oxygen and thereby directly produce H2O2.
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PMID:Altered O2-/H2O2 production ratio by in vitro and in vivo primed human neutrophils. 215 35

The mechanism(s) involved in the generation of free radicals in human leukocytes by cis-unsaturated fatty acids, gamma-linolenic acid (GLA), and arachidonic acid (AA), was investigated. Calmodulin antagonists, chlorpromazine and trifluoperazine, inhibited free radical generation by human leukocytes in vitro induced by GLA, AA PMA (Phorbol myristate acetate), formyl-methionyl-leucyl-phenylalanine (FMLP) and lipopolysaccharide (LPS). On the other hand, chloroquine, a phospholipase A2 inhibitor, and colchicine, a microtubule disrupting agent, were without any effect. When sub-optimal concentrations of GLA and AA were added together, leukocytes showed an additive effect on free radical generation. These results indicate that Calmodulin dependent event(s) play a significant role in the generation of free radicals by human leukocytes.
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PMID:Free radical generation in human leukocytes by CIS-unsaturated fatty acids is a calmodulin dependent process. 216 83


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