Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet activating factor acetylhydrolase (PAF-AH) activity was measured in patients with sepsis, and its relationships with various cytokines and endotoxin were evaluated. PAF-AH activity was significantly higher (p = 0.0136) in 17 patients who died than 13 patients who survived. PAF-AH activity showed significant correlations with the plasma endotoxin, TNF-alpha, and IL-8 levels. These findings suggest that PAF-AH activity reflects the severity of the pathological condition.
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PMID:Platelet-activating factor (PAF) acetylhydrolase activity, type II phospholipase A2, and cytokine levels in patients with sepsis. 800 78

PLA2 is a family of regulatory enzymes that control eicosanoid synthesis and PAF production. PLA2 must be tightly regulated within the cell or cell destruction results. Circulatory release of PLA2 occurs in states of profound illness including sepsis, shock, severe injury, and pancreatitis, all of which are linked to the development of ARDS and MOF. Experimental and clinical evidence suggests that PLA2 may serve a primary regulatory role in the development of these inflammatory disorders. This evidence suggests that inhibitors of PLA2 activation could play an important role in future intensive care management.
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PMID:Phospholipase A2 regulates critical inflammatory mediators of multiple organ failure. 812 Nov 78

There is no satisfactory assay procedure of PAF in human whole blood in terms of sensitivity, reproducibility and simplicity. This is due to coexisting lipids from plasma and cellular membranes which inhibit measurement of PAF in various assay procedures, including bioassay. In the present study, an attempt was made to eliminate these interfering lipid inhibitors from blood samples. Lipids in human whole blood were extracted according to the method of Bligh & Dyer and the organic layer was dried under a stream of nitrogen. Then, the dried organic layer was dissolved in diethyl-ether and the solution was kept at -20 degrees C which was then centrifuged. The resulting supernatant was then applied to an anion-exchange column and the PAF fraction was obtained by step-wise gradient elution. The fraction was further purified by normal phase HPLC. Then PAF in the final sample was determined by sensitive bioassay using rabbit platelets containing fibrinogen and epinephrine. The recovery rate of PAF throughout this procedure was constant and satisfactory (37.4 +/- 9.7%), which was confirmed using [3H]-PAF. The lower limit of the present assay was estimated to be 5pg in 1 ml of blood and it was sensitive enough to detect PAF in blood samples from healthy volunteers and patients with sepsis or liver cirrhosis. Furthermore, attempts were made to compare the sensitivity and the recovery of our method with these of a commercially available radioimmunoassay (RIA) kit for PAF. However, it was not possible to detect any amount of authentic PAF added to whole blood.
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PMID:A new method of purification and sensitive bioassay of platelet-activating factor (PAF) in human whole blood. 829 90

During sepsis, the systemic inflammatory response is characterized by the release of numerous mediators supporting and dispersing inflammation. In Gram negative sepsis, the endotoxins play a starting role, while in other sepsis, the triggering mediators or mechanisms are unknown but lead to a similar inflammatory reaction. Coagulation and complement cascades are activated, with the release of chemoattractive substances, mediators and proteases and the activation of phagocytic cells. Macrophages/monocytes and polymorphonuclear leucocytes produce then active oxygen species and cytokines; they degranulate (releasing active enzymes such as myeloperoxidase), they express an increasing number of membrane receptors able to interact with endothelial cells and release a supplementary lot of inflammatory mediators (prostanoids, platelet activating factor, leukotrienes ... ). Platelets, also activated, produce the same mediators (TXA2, PAF ...) or specific ones such as serotonine, platelet factor 4, growth factors. Last, but not least, the endothelial cells are stimulated, directly (by endotoxins) or undirectly (by cytokines, C5a, PAF ...). These cells play then a main role by their own phagocytic activity, by alteration of their antithrombotic and fibrinolytic potential, by their secretion of inflammatory mediators and by an increased expression of receptors of adhesivity for the activated phagocytes or platelets, what leads to endothelium injury with membrane permeability alterations. These cascades of activation, these extensions of the inflammatory reaction by the mediators and by the phagocytes and platelets can explain the frequency of multiple organ failure during sepsis as well as the difficulty of an adequate pharmacological therapy.
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PMID:[Other mediators of inflammation and sepsis]. 846 93

Mortality from sepsis is still unacceptably high which justifies a new therapeutic approach complementary of antibiotics and symptomatic treatment. Recent advances in the understanding of sepsis and septic shock opened new fields of therapeutic intervention. Nevertheless, there are so many potential targets that is hard to make a choice for evaluation of these new agents: anti-endotoxin (monoclonal antibodies, lipid A analogs, BPI), anticytokines (monoclonal antibodies, soluble receptors, IL-1 receptor antagonist), anti-inflammatory agents (non-steroidal anti-inflammatory agents, anti-PAF, reactive oxygen radicals scavengers...), extracorporeal removal of toxic molecules, inhibition of the adhesion of polymorphonuclear leucocytes on endothelial surface, optimisation of general and regional circulation. The use of these new and often costly drugs must rely on multicenter randomized clinical trials since extrapolation to the human of experimental data gathered in animal studies are hazardous.
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PMID:[Therapeutic perspectives of severe infectious states]. 846

Multiple organ dysfunction syndrome (MODS) is a critical condition developing in the patients under overwhelming surgical insults such as a major surgery, severe trauma, extensive burn, and systemic sepsis. The host response to those surgical insults is the main pathogenetic factor contributing to the development of shock and MODS seen in surgical patients. The proinflammatory cytokines, TNF-alpha (TNF) and interleukin-1 beta (IL-1), are known to play a pivotal role in the pathogenetic mechanisms of MODS. In response to surgical insults, macrophages produce and release TNF and IL-1 which subsequently induce the production of other cytokines (IL-6, IL-8, etc.) and other endogenous chemical mediators (growth factors, adhesion molecules, complement cleavage products, thrombin, eicosanoids, PAF, nitric oxides, oxygen-free radicals, granulocyte elastase, etc.) The resultant systemic inflammation may develop into shock and MODS when the primary insults are overwhelming (early MODS) or a second inflammatory insult such as sepsis triggers an exaggerated inflammation. In the patients suffering from MODS, a systemic release of various cytokines is not properly regulated, and the high blood levels of the proinflammatory cytokines induce an autodestructive generalized inflammatory reaction. This condition is termed "Cytokine Storm" by the author. In the cytokine storm, not only proinflammatory cytokines but also anti-inflammatory cytokines are elevated in the blood stream. With the recent understanding of the biological and pathological roles of cytokines and other mediators, a new therapeutic strategy has been developed. In addition to the reduction of the surgical insults, a variety of anti-cytokine therapy and anti-mediator therapy has been tested in an attempt to prevent or treat the life-threatening MODS.
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PMID:[Cytokine storm in the pathogenesis of multiple organ dysfunction syndrome associated with surgical insults]. 894 Jun 90

Streptococcus pneumoniae can produce asymptomatic colonization or aggressive sepsis. We sought to differentiate the molecular mechanisms of these disparate courses. Cytokine or thrombin activation of human vascular endothelial cells and type II pneumocytes enhanced pneumococcal adherence relative to resting cells. Adherence and subsequent invasion was dramatically reduced by PAF receptor antagonists. Cells transfected with the PAF receptor gained the ability to support pneumococcal adherence. PAF or PAF receptor antagonists inhibited attachment and invasion. Adherence involved phosphorylcholine on the pneumococcal teichoic acid. Virulent pneumococci target the PAF receptor on activated human cells, a necessary step to facilitate subsequent invasion.
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PMID:PAf receptor anchors Streptococcus pneumoniae to activated human endothelial cells. 913 Nov 32

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

Many inflammatory mediators activate neutrophils (PMN) partly by increasing cytosolic calcium concentration ([Ca2+]i). Modulation of PMN [Ca2+]i might therefore be useful in regulating inflammation after shock or sepsis. The hemodynamic effects of traditional Ca2+ channel blockade, however, could endanger unstable patients. Store-operated calcium influx (SOCI) is known now to contribute to Ca2+ flux in "nonexcitable" cells. Therefore, we studied the role of SOCI in human PMN responses to the proinflammatory ligand PAF. PMN [Ca2+]i was studied by spectrofluorometry with and without external calcium. We studied the effects o
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PMID:PAF-mediated Ca2+ influx in human neutrophils occurs via store-operated mechanisms. 1120 69

The platelet-activating factor-acetylhydrolase (PAF-AH) is an enzyme which catalyzes the hydrolysis of acetyl ester at the sn-2 position of PAF. The family of PAF-AHs consists of two intracellular isoforms (Ib and II), and one secreted isoform (plasma). These PAF-AHs show different biochemical characteristics and molecular structures. Plasma PAF-AH and intracellular isoform, II degrade not only PAF but also oxidatively fragmented phospholipids with potent biological activities. Among these PAF-AHs, plasma PAF-AH has been the target of many clinical studies in inflammatory diseases, such as asthma, sepsis, and vascular diseases, because the plasma PAF-AH activity in the patients with these diseases is altered when compared with normal individuals. Finding a genetic deficiency in the plasma PAF-AH opened the gate in elucidating the protecting role of this enzyme in inflammatory diseases. The most common loss-of-function mutation, V279F, is found in more than 30% of Japanese subjects (4% homozygous, 27% heterozygous). This single nucleotide polymorphism in plasma PAF-AH and the resulting enzymatic deficiency is thought to be a genetic risk factor in various inflammatory diseases in Japanese subjects. Administration of recombinant plasma PAF-AH or transfer of the plasma PAF-AH gene improves pathology in animal models. Therefore, substitution of plasma PAF-AH would be an effective in the treatment of the patients with the inflammatory diseases and a novel clinical approach. In addition, the detection of polymorphisms in the plasma PAF-AH gene and abnormalities in enzyme activity would be beneficial in the diagnosis of the inflammatory diseases.
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PMID:Plasma platelet activating factor-acetylhydrolase (PAF-AH). 1254 53


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