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)

Role of platelet-activating factor (PAF) as a potential mediator of hepatic pathophysiology was investigated using a rat model of obstructive jaundice. Over a 1-wk course of bile duct ligation, a sixfold increase in tissue levels of PAF (1.57 +/- 0.43 ng/g vs. control 0.24 +/- 0.08 ng/g) occurred in the liver, whereas no change was observed in PAF levels in plasma. Concomitantly, endotoxin was detected in portal blood drawn from jaundiced rats, and antagonism of the putative effect of endotoxin by neomycin plus polymyxin B reduced local PAF concentrations in livers from jaundiced animals. Induction of neutropenia failed to alter the elevated hepatic PAF concentrations. Moreover, a large quantity of PAF was released spontaneously from Kupffer cells isolated from livers derived from jaundiced rats but not from endothelial cells or hepatocytes from the same animals. An in vitro study using cultured Kupffer cells from normal rats indicated that Kupffer cells secreted a significant amount of PAF in response to lipopolysaccharide challenge; pretreatment of cells with polymyxin B prevented this stimulated PAF release. Treatment of animals with either of two PAF receptor antagonists (BN 52021 and WEB 2170) partially prevented the increase in tissue levels of eicosanoids and O2-derived free radicals and partially alleviated liver injury as judged by the appearance of glutamate-pyruvate transaminase in the plasma of jaundiced rats. The present study indicates 1) that endogenous PAF may be an important signaling mediator for the hepatic inflammatory alterations associated with short-term bile duct ligation and 2) that the interaction of Kupffer cells with portal endotoxin is the mechanism by which PAF is produced locally.
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PMID:Role of platelet-activating factor in hepatic responses after bile duct ligation in rats. 144 33

Bacterial lipopolysaccharide (LPS) promotes transient lung neutrophil sequestration. These LPS-primed neutrophils, when stimulated by an N-formyl peptide (FNLP), promote lung injury. We hypothesized that LPS-primed, FNLP-stimulated neutrophils promote lung injury through a platelet-activating factor (PAF)-dependent mechanism. Rats were pretreated with either saline or WEB2170, a PAF receptor antagonist (10 mg/kg po). One hour after pretreatment, rats were administered intraperitoneal LPS (salmonella typhimurium lipopolysaccharide, 500 micrograms/kg) followed 6 hr later by intravenous FNLP (250 micrograms/kg infused over 30 min). Two hours after the initiation of FNLP infusion, rats were sacrificed and assays were performed to measure: (1) lung neutrophil sequestration with myeloperoxidase (MPO) activity; (2) circulating neutrophil activation with nitroblue tetrazolium (NBT) staining, and (3) lung microvascular leak with 125I-albumin flux. We found that lung myeloperoxidase, circulating neutrophil NBT staining, and lung 125I-albumin flux were increased (P less than 0.05) in saline-pretreated LPS/FNLP rats, relative to control. While lung MPO remained increased (P less than 0.05) in WEB2170-pretreated LPS/FNLP rats, circulating neutrophil NBT and lung 125I-albumin flux were decreased (P less than 0.05) relative to those in saline-pretreated rats. We conclude that PAF mediates LPS/FNLP-induced neutrophil activation and lung injury, but is independent from lung neutrophil sequestration. Thus, lung neutrophil sequestration does not inevitably produce lung injury. Rather, neutrophils can accumulate in the lung without causing lung injury if neutrophil activation can be blocked.
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PMID:Primed neutrophils injure rat lung through a platelet-activating factor-dependent mechanism. 171 5

We tested the hypothesis that lipopolysaccharide (LPS)-induced myocardial dysfunction is mediated by cyclooxygenase-derived metabolites of arachidonic acid or platelet activating factor (PAF). Ether-anesthetized rats were injected iv with normal saline (NS; 2.5 ml/kg), ibuprofen (cyclooxygenase inhibitor; 15 mg/kg), or SDZ 64-688 (PAF receptor antagonist; 5 mg/kg). Thirty minutes later, the rats were injected iv with NS (5 ml/kg) or Escherichia coli 0111:B4 LPS (20 mg/kg). Two hours later, atria were harvested, connected to an isometric force transducer-amplifier-recorder apparatus, and maintained in vitro in oxygenated 37.5 degrees C Krebs--Henseleit buffer. Force of contraction indexed to body weight (FOCI; g/kg) was significantly (P less than 0.05) lower in the NS/LPS group (N = 7) than in the NS/NS group (N = 7). Pretreatment with ibuprofen (ibuprofen/LPS group; N = 8) did not affect the adverse effect of LPS on atrial FOCI. In contrast, pretreatment with SDZ 64-688 (64-688/LPS group; N = 8) ameliorated (P less than 0.05) the deleterious effect of LPS on contractility. The PAF antagonist did not manifest intrinsic positive inotropic activity (64-688/NS group; N = 8). These results support the notion that LPS-induced myocardial dysfunction in the rat is mediated, at least in part, by PAF.
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PMID:Endotoxin-induced myocardial depression in rats: effect of ibuprofen and SDZ 64-688, a platelet activating factor receptor antagonist. 219 72

BN 50739, a new PAF receptor antagonist, was tested in vitro and in vivo for its capacity to block PAF, endotoxin and recombinant human tumor necrosis factor-alpha (rTNF)-mediated effects. In vitro, BN 50739 blocked PAF-induced platelet aggregation by 60 to 100% at 0.2-1 x 10(-7) M (P less than .002), respectively. In the conscious rat, pretreatment (30 min) with BN 50739 (n = 5-13) dose-dependently attenuated PAF-induced hypotension (-5 +/- 5 vs. - 43 +/- 2 mm Hg, P less than .01) and shortened the recovery time of mean arterial pressure (22 +/- 13 vs. 325 +/- 46 sec, P less than .01). BN 50739 (10 mg/kg i.p., n = 5-11) prevented endotoxin (14.4 mg/kg) induced-hemoconcentration (54 +/- 1 vs. 46 +/- 1%, P less than .01) and reduced 24-hr mortality (100 vs. 60%, P less than .05). Only partial protection was conveyed by BN 50739 against the hypotensive response to endotoxin (115 +/- 3 vs. 91 +/- 4 mm Hg, P less than .03). Also, BN 50739 attenuated the lipopolysaccharide-induced elevation of plasma thromboxane B2 (21.2 +/- 0.8 vs. 46.7 +/- 11.8 pg/100 microliters, P less than .01) and tumor necrosis factor-alpha (7523 +/- 3983 vs. 26,430 +/- 3541 U/ml, P less than .05), whereas leukopenia and thrombocytopenia remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet activating factor (PAF) and tumor necrosis factor-alpha (TNF alpha) interactions in endotoxemic shock: studies with BN 50739, a novel PAF antagonist. 221 60

Human Mono Mac 6 cells exhibit characteristics of mature blood monocytes. Treatment of these cells with human recombinant human tumor necrosis factor (TNF) resulted in an increase in phagocytosis and phorbol myristate acetate-stimulated superoxide anion production at 12 h and growth retardation occurring at 24 h. Moreover, TNF induced a moderate increase of CD14 surface antigen expression, used as a phenotypic marker of monocyte/macrophage differentiation. Platelet-activating factor (PAF) stimulated a rapid rise in cytosolic free Ca++ ([Ca++]i) of 308 +/- 93 nM in TNF-treated cells compared to untreated cells (33 +/- 8 nM, n = 4). The effect of TNF was dose and time dependent, evident after 12 h and maximal at 48 h. The enhanced PAF-induced [Ca++]i rise was inhibited by the PAF receptor antagonist L-659,989 and EGTA, indicating receptor-dependent Ca++ influx. Furthermore, L-659,989 and PAF inhibited specific 3H-labeled PAF binding in TNF-treated, but not in untreated cells. Consistently, PAF stimulated arachidonic acid release only in TNF-treated cells. Preincubation of cells with anti-TNF monoclonal antibodies abolished TNF-induced effects, but failed to block lipopolysaccharide (LPS) effects. Distinct mechanisms of action by LPS were reflected by the different ability to induce surface antigen expression. In conclusion, the enhancement of PAF responses by TNF, associated with functional characteristics of differentiation in Mono Mac 6 cells, may represent a specific mechanism of cooperative interaction between PAF and TNF in inflammation, sepsis, immunoregulation and atherogenesis.
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PMID:Tumor necrosis factor induces enhanced responses to platelet-activating factor and differentiation in human monocytic Mono Mac 6 cells. 768 99

This study investigates the role of endogenous platelet-activating factor (PAF) in the production of nitric oxide (NO) by constitutive and inducible isoforms of NO synthase (NOS) in endotoxin shock. In anesthetized rats, 3 hours of endotoxemia resulted in a fall in mean arterial blood pressure (MAP) from 127 +/- 5 (control) to 61 +/- 7 mm Hg and a reduction of the pressor responses to norepinephrine (NE, 1 microgram.kg-1) from 33 +/- 3 (control) to 17 +/- 2 mm Hg. Endotoxemia for 3 hours also resulted in a significant reduction in the contractile effects of NE (10(-8) to 10(-6) mol/L) in thoracic aortas ex vivo. This hyporeactivity to NE was due to an enhanced formation of NO, for it was restored by the NOS inhibitor NG-nitro-L-arginine methyl ester. Animals pretreated with the PAF receptor antagonist WEB 2086 maintained higher MAP (MAP at 180 minutes, 98 +/- 6 mm Hg) and exhibited more pronounced pressor responses to NE at 180 minutes after LPS injection. Moreover, WEB 2086 attenuated by 58% the lipopolysaccharide (LPS)-induced hyporeactivity of the rat aortic rings ex vivo. At 3 hours after LPS injection, calcium-independent NOS activity was induced in the lung. The activity of inducible NOS was significantly lower (by 31%) in lungs of rats pretreated with WEB 2086. The hypothesis that WEB 2086 attenuates the induction of NOS in vivo was substantiated in vitro by the finding that pretreatment with WEB 2086 for 30 minutes inhibited the LPS-stimulated NO production in cultured murine macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet-activating factor contributes to the induction of nitric oxide synthase by bacterial lipopolysaccharide. 769 62

The effect of ST 899, a novel platelet-activating factor (PAF) receptor antagonist, on serum tumor necrosis factor (TNF), interleukin-6 (IL-6), and interferon-gamma (IFN-gamma) production as well as on lethality in an experimental endotoxin shock model was investigated in C57BL/6 mice. In this model, animals receiving 40 mg/kg lipopolysaccharide (LPS) (Escherichia coli 055:B5) intraperitoneally were pretreated with ST 899 administered according to two different schedules. ST 899 pretreatment dose dependently reduced the mortality induced by LPS injection. The PAF receptor antagonist was also able to reduce significantly the LPS-induced increase in serum TNF. Although serum IL-6 levels were not affected, we found that ST 899, when administered intraperitoneally 60 min and intravenously 10 min prior to LPS challenge, had a tendency (at higher doses) to decrease circulating IFN-gamma levels. It is suggested that ST 899 may be beneficial, in combination with current therapies, in the treatment of diseases that involve overproduction of PAF, TNF, and IFN-gamma such as septic shock.
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PMID:Beneficial effects of a novel platelet-activating factor receptor antagonist, ST 899, on endotoxin-induced shock in mice. 775 21

Platelet-activating factor (PAF) has been shown to play an important role in the generation of tumor necrosis factor-alpha (TNF-alpha) and superoxide in guinea pig peritoneal macrophages. In this study, the effects of the PAF receptor antagonists, WEB 2170 and RP 59277, and of a PAF analogue, HAGPT, on TNF-alpha and superoxide production by rat Kupffer cells was investigated. The liver macrophages produced very little TNF-alpha and superoxide when exposed to PAF, but released substantial amounts of superoxide following treatment with zymosan or phorbol 12-myristate 13-acetate (PMA). WEB 2170 not only inhibited the generation of superoxide by PMA but also suppressed the LPS-induced TNF-alpha synthesis by Kupffer cells in a concentration-dependent manner. Northern blot analysis revealed that the expression of TNF-alpha mRNA induced by lipopolysaccharide (LPS) in Kupffer cells was partially abrogated by WEB 2170 or RP 59227. Furthermore, WEB 2170 reduced the PMA-induced leakage of lactate dehydrogenase (LDH) from Kupffer cells in a dose-dependent manner. These data suggest that TNF-alpha and superoxide syntheses in Kupffer cells are rather insensitive to exogenous PAF. On the other hand, the PAF antagonists used in this study interfere with the transduction of the signals induced by LPS, PMA or zymosan. It is questionable whether the PAF receptor of the plasma membrane is involved in the inflammatory response of rat Kupffer cells.
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PMID:Platelet-activating factor antagonists suppress the generation of tumor necrosis factor-alpha and superoxide induced by lipopolysaccharide or phorbol ester in rat liver macrophages. 794 67

Previous studies in animals have shown that lipopolysaccharide produces experimental cholecystitis possibly through a platelet-activating factor-prostanoid mediated process. In this study it was intended to evaluate the effect of LPS on primary cultures of human gallbladder mucosal cells. Gallbladder mucosal cells were isolated from gallbladders removed during routine cholecystectomies or other operations. The cells were cultured for 24 h before treatment. Unstimulated cells produced low levels of prostanoids and significant basal levels of PAF. LPS produced stimulation of eicosanoid and PAF secretion. The increased prostanoid formation was not enhanced when LPS and PAF were administered together. Prostanoid synthesis was inhibited by the administration of a cyclooxygenase inhibitor while administration of a PAF receptor antagonist significantly increased prostanoid formation, suggesting that increased PAF levels function as a negative control mechanism to decrease prostanoid synthesis. The results suggest that endotoxemia may produce a cascade of inflammatory processes in human gallbladder mucosal cells resulting in the development of acute acalculous cholecystitis.
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PMID:Studies on the etiology of acute acalculous cholecystitis: the effect of lipopolysaccharide on human gallbladder mucosal cells. 804 74

Injection of bacterial lipopolysaccharide (LPS) into experimental animals induces septic shock associated with the release of tumor necrosis factor (TNF) and platelet-activating factor (PAF). Because both TNF and PAF stimulate neutrophil adhesion to endothelial cells in vitro, and because neutrophils are important effector cells in sepsis-induced lung vascular injury, the role of TNF and PAF in LPS-induced lung neutrophil sequestration was investigated. Lung myeloperoxidase (MPO) activity was measured as a quantitative assessment of pulmonary leukostasis. Injection of Salmonella enteritidis LPS into rats caused dose-dependent increases in lung MPO that peaked at 2 hours and persisted for up to 24 hours. Injection of purified human recombinant TNF (2 to 200 micrograms/kg i.v.) mimicked the effect of LPS on lung MPO activity. Injection of synthetic PAF increased lung MPO only at the highest and lethal dose (10 micrograms/kg). Lower doses (0.1 and 1 microgram/kg) of PAF had no effect on lung MPO by itself and did not enhance LPS- or TNF-induced lung neutrophil sequestration. Furthermore, pretreatment of the rats with two different PAF receptor-antagonists, WEB 2086 (10 mg/kg IP) and SRI 63-441 (10 mg/kg IP), failed to block LPS-induced (1 mg/kg) increase in lung MPO. These data suggest that TNF, not PAF, mediates LPS-induced pulmonary neutrophil sequestration in the intact rat.
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PMID:Endotoxin-induced pulmonary leukostasis in the rat: role of platelet-activating factor and tumor necrosis factor. 828 63


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