Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipopolysaccharide (LPS) is a known inducer of numerous pro-inflammatory events including the production of platelet-activating factor (PAF). PAF released in response to LPS is a major contributor to the pathological events associated with endotoxemia. The present study demonstrates that dexmethasone (DEX) inhibited the LPS-induced early plasma PAF raise in a dose- and time-dependent manner. In addition, DEX prevented the subsequent PAF-mediated pathological phenomena such as anaphylactic shock-like symptoms, symptoms of disseminated intravascular coagulation and hemorrhage in renal medullae. DEX or the PAF antagonist BN 50739 significantly inhibited LPS-induced NF-kappaB activation. The inhibition of NF-kappaB activation by DEX was overcome by the injection of exogenous PAF. Administration of PAF or LPS resulted in a rapid loss of IkappaBalpha protein. The LPS-induced degradation of IkappaBalpha was prevented by pretreatment with BN 50739, suggesting that PAF is a critical intermediate in the LPS-triggered degradation of IkappaBalpha protein. DEX prevented the LPS-induced IkappaBalpha degradation, which was also reversed by exogenous PAF. Administration of DEX or BN 50739 caused an increase in cytoplasmic IkappaBalpha level. Our results indicate that DEX inhibits IkappaBalpha degradation and subsequent NF-kappaB activation through blocking the initial release of PAF.
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PMID:Glucocorticoids prevent NF-kappaB activation by inhibiting the early release of platelet-activating factor in response to lipopolysaccharide. 1022 1

Endotoxic lipopolysaccharide (LPS) is a proinflammatory agonist produced by gram-negative bacteria and a contributor to the majority of the 400,000 septic shock cases recorded annually in US hospitals. The primary target cells for LPS are monocytes and macrophages. Their response consists of massive production of proinflammatory cytokines, reactive oxygen- and nitrogen-intermediates, procoagulants, and cell adhesion molecules. In turn, expression of these LPS-responsive factors contributes to collapse of the circulatory system, to disseminated intravascular coagulation, and to a 30% mortality rate. A common intracellular mechanism responsible for the expression of septic shock genes in monocytes and macrophages involves the activation of NF-kappaB. This transcription factor is regulated by a family of structurally related inhibitors including IkappaBalpha, IkappaBbeta, and IkappaBepsilon, which trap NF-kappaB in the cytoplasm. In this report, the investigators show that LPS derived from different gram-negative bacteria activates cytokine-responsive IkappaB kinases containing catalytic subunits termed IKKalpha (IKK1) and IKKbeta (IKK2). The kinetics of IKKalpha and IKKbeta activation in LPS-stimulated human monocytic cells differ from that recorded on their stimulation with tumor necrosis factor-alpha, thereby implying a distinct activation mechanism. LPS-activated IKK complexes phosphorylate all 3 inhibitors of NF-kappaB: IkappaBalpha, IkappaBbeta, and IkappaBepsilon. Moreover, LPS activates IKKbeta preferentially, relative to IKKalpha. Thus, IKK complex constitutes the main intracellular target for LPS-induced NF-kappaB signaling to the nucleus in human monocytic cells to activate genes responsible for septic shock.
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PMID:IkappaB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells. 1047 96

Although it has been suggested that some biological activities of platelet-activating factor (PAF) are mediated by, at least in part, reactive oxygen intermediates (ROI), the precise mechanisms underlying the interaction between the two remains to be elucidated. Antioxidants, such as alpha-tocopherol acid succinate, N-acetyl-L-Cysteine, pyrrolidinedithiocarbamate failed to inhibit PAF-induced immediate systemic reactions such as lethality, symptoms of disseminated intravascular coagulation, and histological changes such as pulmonary edema and hemorrhage in renal medullae 10 min following PAF injection. In contrast. antioxidants significantly inhibited both the in vivo and in vitro PAF-induced NF-kappaB activation and NF-kappaB-dependent TNF-alpha expression. The effects of the antioxidants were due to their inhibition of PAF-induced degradation of IkappaBalpha, a protein responsible for keeping NF-kappaB in an inactive form. A protein tyrosine kinase and N-tosyl-L-phenylalanine chloromethyl ketone sensitive serine protease were involved in both PAF- and H2O2-induced NF-kappaB activation. Collectively, these data indicate that the PAF-induced NF-kappaB activation is selectively mediated through the generation of ROI.
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PMID:Selective involvement of reactive oxygen intermediates in platelet-activating factor-mediated activation of NF-kappaB. 1092 4

The serpin antithrombin III (AT III), the most important natural inhibitor of thrombin activity, has been shown to exert marked anti-inflammatory properties and proven to be efficacious in experimental models of sepsis, septic shock, and disseminated intravascular coagulation. Moreover, clinical observations suggest a possible therapeutic role for AT III in septic disorders. The molecular mechanism, however, by which AT III attenuates inflammatory events is not yet entirely understood. We show here that AT III potently blocks the activation of nuclear factor kappaB (NF-kappaB), a transcription factor involved in immediate early gene activation during inflammation. AT III inhibited agonist-induced DNA binding of NF-kappaB in cultured human monocytes and endothelial cells in a dose-dependent manner, suggesting that AT III interferes with signal transduction leading to NF-kappaB activation. This idea was supported by demonstrating that AT III prevents the phosphorylation and proteolytic degradation of the inhibitor protein IkappaBalpha. In parallel to reducing NF-kappaB activity, AT III inhibited the expression of interleukin-6, tumor necrosis factor-alpha, and tissue factor, genes known to be under the control of NF-kappaB. The observation that chemically modified AT III that lacks heparin-binding capacity had no effect on NF-kappaB activation supports the current understanding that the inhibitory potency of AT III depends on the interaction of AT III with heparinlike cell surface glycosaminoglycans. This hypothesis was underscored by the finding that the AT III beta-isoform, known to have higher affinity for glycosaminoglycans, is more effective in preventing NF-kappaB transactivation than alpha-AT III. These data indicate that AT III can alter inflammatory processes via inhibition of NF-kappaB activation.
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PMID:Antithrombin III inhibits nuclear factor kappaB activation in human monocytes and vascular endothelial cells. 1201 Aug 2

Tissue factor (TF) is an important regulator and effector molecule of coagulation in various inflammatory states. In sepsis, expression of TF by activated endothelial cells leads to disseminated intravascular coagulation. Scoparone is extracted from the traditional Chinese herb ARTEMISIA SCOPARIA and is known to have potent anti-inflammatory properties. In the current studies, we examined the effects of scoparone on inhibiting lipopolysaccharide (LPS)-induced TF expression in cultured human umbilical vein endothelial cells (HUVECs). Flow-cytometric analysis revealed LPS (10 micro g/ml)-activated surface TF induction was concentration-dependently inhibited by scoparone (10-400 micro M). The concentrations of scoparone used in this study did not affect cell viability. The elevation of the procoagulant activity of TF by LPS was suppressed by scoparone. The LPS-induced superoxide formation was markedly decreased by scoparone. Messenger RNA expression of TF in LPS-activated HUVECs was also reduced by scoparone. Furthermore, scoparone did not significantly affect the IkappaBalpha degradation. Our results demonstrate that the inhibition of scoparone on LPS-induced TF expression in HUVECs may mediate by the mechanisms suppressing superoxide anion formation and TF transcription.
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PMID:Scoparone inhibits tissue factor expression in lipopolysaccharide-activated human umbilical vein endothelial cells. 1292 92