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)

Thrombomodulin (TM), the endothelial cell surface receptor for thrombin-mediated activation of protein C and of its anticoagulant system, is involved in maintaining vascular nonthrombogenicity, and depressed TM activity may induce intravascular fibrin formation. TM antigen was previously found by immunohistochemical methods in rabbit glomeruli. We therefore attempted to identify the corresponding TM activity in isolated detergent-solubilized rat and human glomeruli. Like purified lung TM, rat glomeruli extracts accelerated the hydrolysis by activated protein C of the chromogenic substrate S-2238 in the presence of 10 nM thrombin, as determined by spectrophotometry. One mg glomerular protein promoted the formation of 681 +/- 115 nmol activated protein C, the equivalent of the amount generated by 845 ng of purified rabbit TM. TM activity correlated with the protein content of the glomerular extracts (r = 0.94). These extracts prolonged rat plasma activated partial thromboplastin time. Incubation of glomeruli with tumor necrosis factor-alpha (TNF) or E. coli lipopolysaccharide depressed their TM-like activity in a dose and time dependent manner. Incubation with TNF suppressed their anticoagulant activity. In human glomeruli, TM activity was also found at a level which corresponded to their TM antigen content, and was determined by ELISA with mouse monoclonal antibody. These results indicate that measurement of glomerular TM activity might help to clarify the mechanisms of intraglomerular fibrin deposition in renal diseases.
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PMID:Quantification and modulation of thrombomodulin activity in isolated rat and human glomeruli. 131 19

Thrombomodulin (TM) is an endothelium-associated glycoprotein that converts thrombin from a procoagulant protease to an anticoagulant. Thrombin, a key enzyme in thrombus formation, binds to TM molecules on endothelium with very high affinity. After binding to TM, thrombin fails to act on the coagulation factors and platelets, and its ability to activate protein C is enhanced more than 1000-fold. We expressed soluble recombinant TM (rTM) in CHO cells and evaluated its antithrombotic effect on thrombin-induced thromboembolism in mice and lipopolysaccharide (LPS) induced disseminated intravascular coagulation (DIC) in rats. Thrombin injection into mouse caused acute thromboembolism resulting instantaneous death, however preinjection of rTM neutralized the lethal effect of thrombin in a dose-dependent manner. Soluble rTM also improved the consumption of fibrinogen and platelets in experimental DIC-rats induced by LPS. The effect of rTM was confirmed in histologically. These data suggest that rTM may have a therapeutic effect on thrombosis or DIC in human.
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PMID:[Therapeutic evaluation of recombinant thrombomodulin]. 133 21

Thrombomodulin is an essential cofactor for the activation of the anticoagulant protein C by thrombin. We have identified the expression of thrombomodulin messenger RNA (mRNA) and protein in peripheral blood monocytes. While untreated monocytes expressed thrombomodulin mRNA by Northern blot analysis, lipopolysaccharide-treated cells had decreased mRNA expression. Thrombomodulin antigen was shown in the cytoplasm and on the surface of monocytes by immunohistochemical staining, and thrombomodulin activity was shown on the surface of intact monocytes. One population of synovial lining cells that normally expressed mononuclear phagocyte antigens also expressed thrombomodulin in both noninflamed osteoarthritic synovium and in inflamed rheumatoid arthritis synovium. However, these cells did not express another endothelial protein, von Willebrand factor. We conclude that both circulating and tissue mononuclear phagocytes are capable of expressing thrombomodulin.
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PMID:Thrombomodulin expression by human blood monocytes and by human synovial tissue lining macrophages. 166 Mar 24

Tumor necrosis factor (TNF) induced by bacterial lipopolysaccharide (LPS) was shown to have an important role in precipitation of septic shock and disseminated intravascular clotting (DIC). At the endothelial level TNF down-regulates thrombomodulin (thus preventing protein C formation) and inhibits the production of tissue plasminogen activator (t-PA), thus impairing anticoagulant mechanisms. On the other hand, TNF up-regulates the production of procoagulant factors such as t-PA inhibitor (PAI), tissue factor and platelet activating factor (PAF). These effects create an imbalance between procoagulant and anticoagulant mechanisms, in favor of the former. TNF also activates polymorphonuclears (PMNs), and increases their chemotaxis and adherence to endothelial surfaces by up-regulation of specific endothelial (ELAM-1) and PMN (CDw18) adherence proteins. The damage inflicted by activated PMN to the endothelial cell promotes tissue factor exposure and PAI release, with initiation of the characteristic explosive coagulation process of DIC, facilitated by the dissociation between pro- and anticoagulant mechanisms induced by TNF. These newly discovered mechanisms precipitating septic shock and DIC enable consideration of new treatments for this condition as anti-TNF antibodies or TNF inhibitors, anti-ELAM-1 antibodies anti-tissue factor antibodies, administration of activated factor C, etc. These therapeutic approaches may revolutionize the treatment of septic shock and DIC in the next decade.
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PMID:Role of tumor necrosis factor in the pathogenesis of intravascular coagulopathy of sepsis: potential new therapeutic implications. 199 4

We have evaluated the quantitative relationship between lipopolysaccharide (LPS, endotoxin), fibrinopeptide A (FPA), antithrombin (AT), protein C (PC) and extrinsic pathway inhibitor (EPI) in plasma from 39 consecutively admitted patients with systemic meningococcal disease (SMD). The most severely ill patients with fulminant meningococcal septicemia (n = 13, 6 dead) had significantly (p less than 0.01) higher plasma levels of LPS and FPA and lower levels of PC and AT on admission as compared with the less severe clinical presentations (n = 26, 1 dead). The levels of EPI on admission were significantly (p less than 0.05) higher in nonsurvivors vs survivors with fulminant septicemia. As the disease progressed, the levels of LPS, FPA, AT and PC declined, while the levels of EPI increased. Three of six nonsurviving septicemic patients had levels of EPI greater than 200% within 16 hours of admission vs two of 30 survivors (p = 0.02). The results suggest that increasing levels of LPS in SMD elicit increasing consumption coagulopathy, contributing to the organ pathophysiology. The kinetics of EPI, inhibiting the thromboplastin-FVIIa-FXa complex, differs markedly from the kinetics of AT and PC i.e. increases as opposed to decreases.
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PMID:The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrinopeptide A in systemic meningococcal disease. 251 Mar 54

A variety of bacterial lipopolysaccharide (LPS) preparations with highly defined primary polysaccharide chemical structure and/or aggregate macromolecular composition have been employed to examine the molecular requirements for activation of the classical and alternative pathways of human serum complement. Evidence is presented for two independent modes of polysaccharide dependent activation of the APC by LPS. One mechanism is dependent upon specific O-antigen polysaccharides and the second is defined by a specific L-glycero-D-mannoheptose/glucose region of the core oligosaccharide. LPS O-antigen polysaccharide but not core oligosaccharide determinants can convert sheep erythrocytes to cells capable of initiating the APC. The data presented provide convincing evidence that the tertiary assembly of individual LPS subunits into an aggregate macromolecule is a critical determinant in the expression of APC activity by LPS. The results of these studies provide strong evidence that CPC activation by LPS is restricted to the Re-chemotype and isolated lipid A. LPS isolated from other R-chemotypes as well as native wild type LPS preparations do not activate the CPC, in spite of the fact that the former LPS preparations contain more lipid A than polysaccharide on a percentage by wt basis. The presence of core polysaccharide L-glycero-D-mannoheptose, which provides a critical recognition role for activation of the APC, appears to negatively regulate CPC activation in a similar inverse relationship. In addition, the presence of polysaccharide containing LPS subunits in synthetic mixed LPS micellar aggregates can also restrict CPC activation by Re LPS subunits, most probably by steric hindrance at the LPS macromolecular surface. Our data are consistent with the hypothesis that activation of either pathway of human serum complement by a given LPS preparation is a mutually exclusive event dictated by the presence or absence of L-glycero-D-mannoheptose.
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PMID:Activation of human serum complement by bacterial lipopolysaccharides: structural requirements for antibody independent activation of the classical and alternative pathways. 330 24

T cell activation is widely believed to depend on interleukin 1 (IL 1) provided by antigen (Ag)-presenting cells (APC). Because IL 1 is not a constitutive product of APC, we examined the features of its production during the interaction of murine T cell clones and APC. We observed that IL 1 was detectable in supernatants of most myoglobin-specific T cell clones grown with APC and Ag. Two of these T cell clones induced exceptionally high levels of IL 1 in their supernatants, and these same clones demonstrated the unusual restriction to I-Ek, which is a low responder type for sperm whale myoglobin. One of these clones was characterized additionally as to the mechanism of IL 1 induction. This clone rapidly stimulated IL 1 production in the APC population (detectable at 4 hr of co-culture) or in macrophages (M phi) or a M phi-like cell line. IL 1 induction was Ag dependent and H-2 restricted. Induction was radioresistant, both on the part of the T cell and of the IL 1 producer. The IL 1-induction process was attributable to a lymphokine produced by the T cell clone. This lymphokine was distinct from IFN-gamma, TNF and CSF-1 and may account for a principal mechanism of T----APC signalling. The induced IL 1 was the same in size, co-mitogenicity, and pyrogenicity as lipopolysaccharide-induced IL 1.
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PMID:IL 1 induction by murine T cell clones: detection of an IL 1-inducing lymphokine. 349 59

Isolated cell envelopes of Pseudomonas aeruginosa were treated with N,N'-dimethylformamide (DMF) or with ethylenediaminetetraacetate (EDTA). DMF solubilized 73% of the dry weight of the cell envelope, 76% of the protein, 78% of the carbohydrate, and 76% of the phosphorus. Electron microscopy showed that DMF caused extensive alterations in the appearance of the cell envelope with blebs and bleblike vesicles predominating. After incubation with EDTA, the cell envelopes appeared to have lost material, but still retained the cell-like morphology. Analysis of DMF-solubilized proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed 16 protein bands. There were three major proteins that predominated, however, with molecular masses of 43,000 (protein A), 16,500 (protein B), and 72,000 daltons (protein C). Evidence is presented that protein A and protein B are glycoproteins. Gel electrophoresis of EDTA-solubilized material revealed that a number of proteins were released from the cell envelope. However, electrophoresis of an isolated protein-lipopolysaccharide complex released by EDTA showed that protein A and protein B were the major protein components of this complex. These data suggest that protein A and protein B are components of the outer cell wall membrane of P. aeruginosa. There is suggestive evidence that these proteins may play a role in maintaining the structural integrity of the cell envelope. Whether these proteins also have enzymatic activity could not be discerned from the present study, although it is possible that they may be associated with the terminal stages of lipopolysaccharide synthesis.
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PMID:Proteins released from cell envelopes of Pseudomonas aeruginosa on exposure to ethylenediaminetetraacetate: comparison with dimethylformamide-extractable proteins. 463 46

We investigated the effect of activated protein C (APC) on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats to investigate the possible usefulness of APC as a treatment for adult respiratory distress syndrome. Intravenously administered LPS (5 mg/kg) significantly increased pulmonary vascular permeability. APC prevented the LPS-induced increase in pulmonary vascular permeability observed at 6 hours. Heparin plus antithrombin III (ATIII) and active site-blocked factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, inhibited LPS-induced coagulopathy but did not prevent LPS-induced pulmonary vascular injury. LPS-induced pulmonary vascular injury was significantly attenuated in rats with nitrogen mustard-induced leukocytopenia and in rats treated with ONO-5046, a potent granulocyte elastase inhibitor. Administration of LPS also increased pulmonary accumulation of leukocytes, as evaluated by measurement of myeloperoxidase activity in the lungs. APC significantly reduced LPS-induced increases in pulmonary accumulation of leukocytes at 1 hour. Neither ATIII plus heparin nor DEGR-Xa inhibited leukocyte accumulation. Active site-blocked APC (DIP-APC) prevented neither the LPS-induced pulmonary accumulation of leukocytes nor the LPS-induced increase in pulmonary vascular permeability. These results suggest that the mechanism of APC inhibition of LPS-induced pulmonary vascular injury was independent of its anticoagulant activity and was related to its ability to inhibit accumulation of leukocytes. In addition, these findings suggest that the serine protease activity of APC may be essential to its inhibitory effect on LPS-induced pulmonary accumulation of leukocytes and subsequent pulmonary vascular injury.
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PMID:Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. 855 86

T cell hybridomas were generated from a LEW rat T cell line specific for the uveitogenic peptide bov-B1 of bovine retinal S-antigen. Using these autoreactive hybridomas, IL-2 production and activation-induced cell death (AICD) were dissociated as outcomes of activation. The self-reactive hybridomas secrete IL-2 and undergo AICD in response to antigen presented by non-irradiated syngeneic splenocytes, whereas antigen presentation by irradiated splenocytes induced only AICD. IL-2 production by a non-self reactive hybridoma was unaffected by irradiation of the APC. Pretreatment of the APC with phorbol ester or lipopolysaccharide and IL-4 protected their ability to induce IL-2 secretion after gamma-irradiation. Although the co-stimulation-blocking reagent CTLA-4-Ig mimicked the effect of gamma-irradiation by preventing IL-2 secretion but not AICD, B7 expression on the APC was not radiosensitive, nor did co-stimulation, provided 'in trans' with a B7-expressing third-party cell, reconstitute antigen-specific hybridoma IL-2 secretion in response to irradiated APC. In summary, the data show that IL-2 secretion and AICD of a self-reactive T cell hybridoma can be dissociated as consequences of TCR occupancy in the presence of a functional co-stimulatory signal. It is proposed that the signals producing these events are transduced through the TCR-CD3 complex alone and reflect the differential outcomes of high- and low-affinity interactions.
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PMID:A radiosensitive APC activity dissociates IL-2 secretion and activation-induced cell death by autoreactive T cell hybridomas. 858 77


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