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)

The intravenous administration of lipopolysaccharide (LPS) to rats results in liver lesions characterized by the infiltration of both platelets and neutrophils into the liver and by midzonal hepatocellular necrosis. The liver injury is dependent on neutrophils, platelets and the coagulation system, as removal or inhibition of any of these components inhibits the development of hepatocellular necrosis. Platelet activating factor (PAF) and the cysteinyl leukotrienes (LTs) are potent inflammatory lipids that are critical for the development of some LPS-mediated alterations. To test the hypothesis that PAF, alone or in combination with LTs, contributes to the development of liver injury during LPS exposure, we conducted studies with the PAF receptor antagonist, WEB 2086, and the 5-lipoxygenase inhibitor, Zileuton. Female, Sprague-Dawley rats were pretreated with WEB 2086 (10 mg/kg, i.p.) alone or with Zileuton (40 mg/kg, p.o.) 1 h before the administration of LPS (4 mg/kg, i.v.) or its saline vehicle. Treatment with WEB 2086, alone or in combination with Zileuton, did not inhibit LPS-mediated hepatic neutrophil infiltration or liver injury, as assessed by histologic evaluation and increases in plasma alanine aminotransferase activity. Pretreatment with these agents also had no effect on the activation of the coagulation system or on the thrombocytopenia induced by LPS. These results suggest that PAF, alone or in combination with 5-lipoxygenase products, is not a critical mediator of LPS-induced hepatocellular injury in this model.
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PMID:Neither platelet activating factor nor leukotrienes are critical mediators of liver injury after lipopolysaccharide administration. 923 96

The cell wall is a key inflammatory agent of gram-positive bacteria. Possible receptors mediating cell wall-induced inflammation include CD14 and platelet-activating factor (PAF) receptor. To delineate the conditions under which these various receptors might be used, human monocytic THP-1 cells and heparinized whole human blood were stimulated with lipopolysaccharide (LPS), intact Streptococcus pneumoniae bacteria, or purified pneumococcal cell wall. THP-1 culture supernatant or cell-free plasma was analyzed for the presence of tumor necrosis factor, interleukin-1beta (IL-1beta), and IL-6. For the cultured monocytes, anti-CD14 inhibited induction of the inflammatory cytokines by the cell wall and LPS but not by intact pneumococcal bacteria. Despite the difference in CD-14 usage, the intracellular pathways induced by the three agents demonstrated similarities, as revealed in the presence of specific signal transduction inhibitors such as cholera toxin, pertussis toxin, and genistein. Cytokine production in whole human blood indicated that anti-CD14 failed to block responses to cell wall and intact pneumococci, whereas while LPS-induced responses were inhibited. PAF receptor antagonist had no effect under any conditions in both assays. These results indicate that although cell walls bind to both CD14 and PAF receptor, only CD14 appears to engender a cytokine response under restricted conditions. Furthermore, host cell responses to intact pneumococci are consistently independent of CD14 and PAF receptor.
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PMID:Coexistence of CD14-dependent and independent pathways for stimulation of human monocytes by gram-positive bacteria. 923 83

We tested the concept that tumor necrosis factor-alpha (TNF-alpha) or platelet-activating factor (PAF) mediated Escherichia coli endotoxin lipopolysaccharide (LPS)-induced upregulation of nitric oxide (NO) and acute-phase hypotension (APH) in the rat. LPS (0.5 mg/kg i.v.) given to rats treated with saline or nonimmune goat-derived gamma-globulin (immunoglobulin G, 22 mg/kg i.m.) produced APH and increased plasma concentrations of TNF-alpha and nitrate and nitrite anions (reactive nitrogen intermediates; RNI) and NO in ex vivo incubates of polymorphonuclear neutrophils (PMN) and inducible NO synthase (iNOS) mRNA in PMN. Pretreatment of rats with a polyclonal TNF-alpha antibody (TNF-Ab, 22 mg/kg i.m.) abolished LPS-mediated increases in plasma TNF-alpha but failed to inhibit APH or the NO system. TNF-alpha (8.2 micrograms/kg i.v.) produced transient hypertension and sustained tachycardia and increased plasma TNF-alpha and PMN iNOS mRNA but not RNI. LPS and TNF-alpha decreased spontaneous and calcimycin (Ca2+ ionophore, 1 microM)- and PAF (1 microM)-mediated increases in head-space NO production by rings of mesenteric artery incubated ex vivo. TNF-Ab abolished all effects of TNF-alpha. PAF (25, 50, and 100 ng/kg) produced APH without increasing plasma TNF-alpha, RNI, or PMN iNOS mRNA. The PAF receptor antagonist BN-50730 (80 micrograms/kg i.v.) abolished PAF-induced APH and attenuated LPS-induced increases in RNI. We conclude that 1) LPS produces parallel but unrelated changes in TNF-alpha and RNI in plasma and PMN during the APH of endotoxemia; and 2) endogenous TNF-alpha is not required for LPS-mediated induction of iNOS mRNA, and PAF mediates LPS-induced APH.
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PMID:Dissociation of TNF-alpha from endotoxin-induced nitric oxide and acute-phase hypotension. 924 87

Apoptosis in vivo is followed almost inevitably by rapid uptake into adjacent phagocytic cells, a critical process in tissue remodeling, regulation of the immune response, or resolution of inflammation. Phagocytosis of apoptotic cells by macrophages has been suggested to be a quiet process that does not lead to production of inflammatory mediators. Here we show that phagocytosis of apoptotic neutrophils (in contrast to immunoglobulin G-opsonized apoptotic cells) actively inhibited the production of interleukin (IL)-1beta, IL-8, IL-10, granulocyte macrophage colony-stimulating factor, and tumor necrosis factor-alpha, as well as leukotriene C4 and thromboxane B2, by human monocyte-derived macrophages. In contrast, production of transforming growth factor (TGF)-beta1, prostaglandin E2, and platelet-activating factor (PAF) was increased. The latter appeared to be involved in the inhibition of proinflammatory cytokine production because addition of exogenous TGF-beta1, prostaglandin E2, or PAF resulted in inhibition of lipopolysaccharide-stimulated cytokine production. Furthermore, anti-TGF-beta antibody, indomethacin, or PAF receptor antagonists restored cytokine production in lipopolysaccharide-stimulated macrophages that had phagocytosed apoptotic cells. These results suggest that binding and/or phagocytosis of apoptotic cells induces active antiinflammatory or suppressive properties in human macrophages. Therefore, it is likely that resolution of inflammation depends not only on the removal of apoptotic cells but on active suppression of inflammatory mediator production. Disorders in either could result in chronic inflammatory diseases.
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PMID:Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. 946 84

The trafficking of monocytes across the endothelial lining of the blood vessel increases in response to bacterial infection at sites of inflammation. However, the molecular events involved in the diapedesis of monocytes in response to endotoxin are not completely understood. Our studies revealed that signaling by lipopolysaccharide (LPS) in human umbilical vein endothelial cells (HUVEC) resulted in a threefold increase in the transendothelial migration of monocyte-like HL-60 cells and a sevenfold increase in the phosphorylation of platelet endothelial cell adhesion molecule-1 (PECAM-1). The transmigration induced by LPS was inhibited by an antibody to PECAM-1. Both the phosphorylation of PECAM-1 and transendothelial migration of monocytes were inhibited by a platelet-activating factor (PAF) receptor antagonist, indicating the autocrine effect of PAF in these events. Treatment of HUVEC with LPS caused a fourfold increase in PAF receptor mRNA expression that was completely blocked by the PAF receptor antagonist. We conclude that PAF, generated by HUVEC in response to LPS or gram-negative bacterial infection, acts in an autocrine manner, causing PECAM-1 phosphorylation and thus the transendothelial migration of monocytes.
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PMID:Endotoxin-induced migration of monocytes and PECAM-1 phosphorylation are abrogated by PAF receptor antagonists. 972 15

The inhibitory effects of YM264, a selective platelet activating factor (PAF) receptor antagonist, and 2-(3-methylsulfonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-( 3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (compound 1), a neutrophil elastase inhibitor, on mortality, and pancreatic, hepatic, renal and pulmonary dysfunction were evaluated in a rat model of multiple organ failure (MOF) accompanying acute pancreatitis. MOF was produced by intraperitoneal injection of lipopolysaccharide (LPS, 30 mg/kg) in rats with cerulein-induced pancreatitis. LPS dose-dependently increased the mortality in rats with or without pancreatitis. The threshold dose which produced death in rats without pancreatitis was 30 mg/kg. This same dose evoked death in more than 40% of rats with pancreatitis. Time-course changes in serum enzyme and organ myeloperoxidase (MPO) levels were first examined in rats with induced MOF, and the results were compared with those in rats treated with only LPS or cerulein. Pancreatic weight, and serum amylase and lipase levels significantly increased in rats with cerulein-induced pancreatitis despite the presence or absence of LPS, but recovery of these pancreatic dysfunctions was slower in the group given LPS. However, serum GOT, GPT, BUN and creatinine levels were significantly elevated only in MOF rats. In the MOF rats, the MPO level in the lung was significantly elevated and arterial oxygen pressure was decreased, indicating that infiltration of neutrophils into the lung might be involved in pulmonary dysfunction. However, the MPO levels in the pancreas and kidney in the MOF rats were not remarkably different from those in normal rats. The inhibitory effects of YM264 and compound 1 on mortality and organ dysfunction were examined in this MOF model. The 24-h survival rate for rats prophylactically and therapeutically treated with an intravenous infusion of YM264 at 0.1 mg/kg h was significantly higher than that of controls. The 24-h survival rate for rats treated prophylactically by intravenous infusion of 2 mg/kg h of compound 1 was significantly higher than that of control, whereas a beneficial dose of compound 1 was 5 mg/kg h in therapeutically treated rats. Prophylactic treatment with YM264 (0.1 mg/kg h) and compound 1 (2 mg/kg h) ameliorated organ dysfunction in rats with MOF. In conclusion, pancreatic, hepatic, renal and pulmonary dysfunctions are observed in this rat MOF model. The PAF receptor antagonist and neutrophil elastase inhibitor reduce the mortality rate in rats with MOF due to their inhibitory effects on organ dysfunction, indicating that PAF and neutrophil elastase may play important roles in the development of MOF. These results in the present model are largely consistent with those in patients with MOF, indicating that this model is suited for MOF in humans and may be used as a model to test new therapeutic approaches.
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PMID:Protective effects of a PAF receptor antagonist and a neutrophil elastase inhibitor on multiple organ failure induced by cerulein plus lipopolysaccharide in rats. 975 12

The effects of ginkgolide A (CAS 15291-75-5, BN52020, GA) and B (CAS 15291-77-7, BN52021, GB) on interleukin (IL)-1, tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) production in resting and lipopolysaccharide (LPS)-stimulated neonatal rat microglia were studied. Apafant (CAS 105219-56-5), a platelet activating factor (PAF) antagonist of triazolobenzodiazepine type was used as control. The biological activities of IL-1 and TNF-alpha were tested by mouse thymocyte proliferation and L929 cytotoxicity assay, respectively. NO concentration was represented by nitrite and determined by Griess reaction. GA 1 nmol/1-10 mumol/l inhibited IL-1 production, and 100 nmol/l-10 mumol/l decreased TNF-alpha and NO production in dose-dependent manner. GB inhibited IL-1, TNF-alpha and NO production at the concentrations 10 nmol/l-10 mumol/l, 100 nmol/l-10 mumol/l and 10 nmol/l-10 mumol/l, respectively. Apafant inhibited IL-1, but not TNF-alpha and NO production. GB plus apafant (50 mumol/l) showed IL-1 and NO inhibitory effects, but not on TNF-alpha. The manner was different from that of GB or apafant alone. The results suggested that GA and GB inhibited proinflammatory cytokines and NO production from LPS-stimulated rat microglia, however, apafant inhibited IL-1 production only. The effects of GA and GB on proinflammatory cytokines and NO production from rat microglia do not seem to be based on PAF receptor antagonism. In addition, GA and GB are regarded as promising agents for the treatment of some neurodegenerative diseases in the central nervous system.
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PMID:Effects of ginkgolides on interleukin-1, tumor necrosis factor-alpha and nitric oxide production by rat microglia stimulated with lipopolysaccharides in vitro. 989 25

Platelet-activating factor (PAF) has been shown to be an important mediator in the pathogenesis of lipopolysaccharide (LPS)-induced liver injury in regenerating rat livers. Both LPS and PAF activate nuclear factor-kappa B (NF-kappaB), a key transcription factor for tumor necrosis factor-alpha (TNF-alpha) and cytokine-induced neutrophil chemoattractant (CINC). The aim of this study is to investigate how PAF participates in the LPS-induced and NF-kappaB-mediated regulation of TNF-alpha and CINC in regenerating rat livers. LPS (1.5 mg/kg) was intravenously administered into 70% hepatectomized rats and sham-operated rats 48 hours postoperatively. LPS administration caused a high mortality rate, scattered necrosis in the liver with infiltration of CINC-positive neutrophils, and a continuous CINC messenger RNA up-regulation and activation of NF-kappaB in the liver only in hepatectomized rats. These phenomena were all effectively prevented by pretreatment and posttreatment with a PAF receptor antagonist, TCV-309. Hepatectomized rats showed NF-kappaB staining in hepatocytes, Kupffer cells, and neutrophils around necrosis 4 hours after the LPS injection, representing the activation of this factor in these cells. Based on these results, we propose that PAF contributes to continuous CINC up-regulation and NF-kappaB activation via accumulation and activation of neutrophils, and thereby is involved in LPS-induced liver injury in regenerating rat livers.
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PMID:Participation of platelet-activating factor in the lipopolysaccharide-induced liver injury in partially hepatectomized rats. 1049 48

Excessive nitric oxide (NO) generated by hepatic cells in response to lipopolysaccharide (LPS) and inflammatory substances (e.g., platelet-activating factor [PAF]) is a key contributor to the pathophysiological outcomes observed in the liver during sepsis. In rats subjected to liver-focused endotoxemia, inducible nitric oxide synthase (iNOS) levels in the intact liver were elevated by 6 hours; cell-specific expression of iNOS messenger RNA (mRNA) was Kupffer cells (KCs), endothelial cells, and hepatocytes. Elevated serum alanine transaminase (ALT) levels at 6 hours confirmed hepatic damage. Pretreatment of endotoxemic rats with PAF receptor antagonists BN 50739 or WEB 2170 reduced serum ALT and iNOS mRNA levels in the intact liver. Pretreatment of cultured KCs with BN 50739 or WEB 2170 inhibited both LPS and PAF-induced iNOS mRNA formation. In addition, LPS-induced iNOS protein levels in KCs pretreated with BN 50739 or WEB 2170 were decreased. Exposure of KCs to either LPS or PAF caused the translocation of the p65 subunit of nuclear factor kappa B (NF-kappaB) into the nucleus and this process was attenuated by BN 50739 and WEB 2170. There was concomitant inhibition of LPS-dependent degradation of the inhibitory protein IkappaBalpha and increase in intracellular Ca(2+) in KC treated with BN 50739 or WEB 2170. Also, in KCs, LPS was able to induce iNOS mRNA expression independent of CD14. This response was inhibited by pretreatment of KCs with either BN 50739 or WEB 2170. Our findings indicate that PAF receptor antagonists convey protection against hepatocellular injury accompanied by a decrease in nitric oxide (NO) formation in the livers of endotoxemic rats.
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PMID:Suppression of lipopolysaccharide-induced nitric oxide synthase expression by platelet-activating factor receptor antagonists in the rat liver and cultured rat Kupffer cells. 1053 42

We characterised early circulatory and respiratory responses to lipopolysaccharide from E. coli (LPS, serotype 0127:B8) in the isolated, ventilated and perfused rat lung preparation. Lungs were isolated from anaesthetised Wistar rats and perfused with full blood, platelet rich plasma (PRP), platelet poor plasma (PPP) or Krebs-Henseleit solution (KH). LPS (300 microg/ml) injected into the blood-perfused lung induced a characteristic biphasic response consisting of an immediate, transient decrease in respiratory tidal volume and an increase in pulmonary perfusion pressures followed by a delayed decrease in respiratory tidal volume. An immediate respiratory/circulatory response to LPS was of considerable magnitude only in full blood-perfused lung whereas the delayed response was fully expressed irrespective whether blood, PRP, PPP or KH was used for the lung perfusion. Immediate respiratory/circulatory response was inhibited by WEB 2170 (100 microM), a PAF receptor antagonist, and by camonagrel (300 microM), a TXA2 synthase inhibitor, but not by MK 571 (100 microM), a cysteinyl leukotriene receptor antagonist. Delayed respiratory response was inhibited by camonagrel only. In summary, we demonstrated that the immediate coupled respiratory/circulatory response is mediated by blood cell-derived PAF and TXA2 whereas the delayed uncoupled respiratory response is mediated by lung parenchyma-derived TXA2.
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PMID:Biphasic response to lipopolysaccharide from E. coli in the isolated ventilated blood-perfused rat lung. 1063 6


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