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)

The effects of adrenaline and isoproterenol, a specific beta-adrenergic agonist, on TNF production were investigated. Both agents inhibited the production of TNF by human blood and THP-1 cells stimulated by LPS. The effect of adrenaline was prevented by a beta-receptor antagonist, but not by an alpha-receptor antagonist. Levels of TNF mRNA were not reduced by adrenaline. Inhibition of TNF production was observed only if cells were first exposed to adrenaline or isoproterenol at about the same time as to LPS; incubation of THP-1 cells with isoproterenol for 24 h before LPS stimulation dramatically increased response, and prevented suppression of TNF production by a second dose of isoproterenol. Intracellular cAMP levels were increased by adrenaline and isoproterenol, at concentrations that inhibited TNF production. However, prolonged incubation of THP-1 cells with isoproterenol resulted in depression of cAMP concentrations to below basal levels. These data suggest that TNF production can be regulated by beta-receptor stimulation, that such regulation is mediated by changes in intracellular cAMP concentrations and is exerted at a posttranscriptional level. Adrenaline may be an important endogenous regulator of TNF production in sepsis.
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PMID:Regulation of tumor necrosis factor production by adrenaline and beta-adrenergic agonists. 135 Feb 91

Previous studies have shown that thrombomodulin (TM) on endothelial cells is down-regulated by endotoxin, interleukin-1 beta (IL-1 beta), and tumor necrosis factor (TNF). This loss of anti-coagulant potential is thought to be related to the hypercoagulable state in sepsis, inflammation, and cancer. The current studies describe up-regulation of TM in human umbilical vein endothelial cells (HUVECs) by several compounds as judged by increased surface cofactor activity, surface TM antigen, and TM mRNA levels. Surface TM activity was increased by active phorbol esters (10(-8) M, 24-48 h), analogs of cAMP (1-10 mM, 4 h), and forskolin (10(-5) M, 24-48 h). Up-regulation of TM in HUVECs by 4 beta-phorbol 12-myristate 13-acetate (PMA) and dibutyryl cAMP (dBcAMP) was due to de novo synthesis of TM protein resulting from increased TM mRNA levels. The results suggest that protein kinase C and protein kinase A may be involved in cellular regulatory mechanisms for TM expression. In addition, PMA effects on surface TM activity are biphasic, with an initial reduction followed by a significant enhancement. Hence, we propose that compounds capable of increasing intracellular cAMP concentrations in HUVECs may be useful in preventing thrombosis by increasing the anti-thrombotic properties of endothelial cells.
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PMID:Up-regulation of thrombomodulin in human umbilical vein endothelial cells in vitro. 196 58

Pertussis toxin, and also cholera toxin are capable of inhibiting the effects of LPS in the elicitation of the generalized Schwartzman reaction. This is a potentially lethal generalized thrombo-haemorrhagic hypersensitivity and inflammatory-type response that occurs after two consecutive injections of LPS. The two exotoxins furnish significant protection against the lethal outcome of this reaction. It is known that the acute haematological and haemodynamic changes are accompanied by alterations in the levels of various endogenous mediators: glucocorticoid hormones, prostaglandins, arachidonic acid metabolites, cytokines and proteases. In vitro effects of LPS on murine leukocyte cell lines can be antagonized by pertussis toxin, implicating a Gi-like regulatory protein in the mediation of these effects. Experiments designed to study the involvement of particular second messenger systems (cAMP and phosphatidylinositol) used by LPS in vivo, revealed that the protective effects conferred by these exotoxins are associated with the antagonization of alterations caused by LPS. No correlation was found between the levels of IL-6 and the mortality rate in this experimental mouse model. The results indicate that G proteins play a role in the generation of the Schwartzman reaction and open a new approach for pharmacological intervention in endotoxemia and in clinical settings with Gram-negative sepsis.
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PMID:Cholera and pertussis exotoxins protect mice against the lethal Schwartzman reaction and antagonize the effects of lipopolysaccharide on second messenger systems. 216 28

Our laboratory has previously shown that the administration of tumor necrosis factor (TNF), a cytokine produced by activated mononuclear cells, to guinea pigs produces a syndrome similar to gram-negative sepsis or ARDS. Pentoxifylline (PTX), a methylxanthine, protects against TNF-induced and sepsis-induced acute lung injury in vivo. We now report on in vitro cellular studies of PMN-mediated cellular injury and its attenuation. We studied TNF-induced bovine pulmonary artery endothelial cell (EC) cytotoxicity both with and without PMN. A 51Cr release assay was used to measure EC damage. Further, we investigated PMN function in response to TNF by measuring chemiluminescence. Agents that attenuate EC damage and PMN activation were evaluated in the above assays. Results revealed that TNF causes EC injury (p less than 0.05) and PMN increase TNF-induced EC injury. Furthermore, PTX, aminophylline (AMPH), caffeine, and forskolin attenuate TNF-induced EC cytotoxicity only in the presence of PMN (p less than 0.05). Of interest, dibutyryl cAMP (DBcAMP) protects EC from TNF-induced injury both with and without PMN. Agents that may increase cAMP levels in PMN (PTX, DBcAMP, forskolin, isobutyl methylxanthine, and terbutaline) significantly attenuate TNF-induced PMN chemiluminescence (p less than 0.05). We conclude that TNF causes EC damage and PMN increase this damage. Furthermore, PTX, AMPH, caffeine, and forskolin can attenuate TNF-induced EC injury in the presence of PMN, whereas DBcAMP attenuates TNF-induced EC injury with and without PMN. In addition, agents that may increase intracellular cAMP levels in PMN can attenuate TNF-induced PMN chemiluminescence. Thus, these agents likely attenuate TNF-induced PMN-mediated EC injury through their inhibitory effects on PMN.
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PMID:Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemiluminescence. 217 54

Burn injury-induced changes at the neuromuscular junction include muscle weakness and altered response to neuromuscular blocking drugs. Protein malnutrition and sepsis can concomitantly occur with burn trauma. The role of pure malnutrition or sepsis, in the absence of burn injury, in inducing neuromuscular changes was studied in the mouse gastrocnemius muscle. Additionally, cAMP levels in muscle were evaluated to reflect metabolic activity. Sepsis was studied using doses of endotoxin at one-fourth or one-third the dose evoking 50% lethality. Diets of 5% protein and 5% protein + 35% fiber achieved protein and protein/calorie malnutrition, respectively. In each model neuromuscular function was evaluated by maximal tension developed. Pharmacologic responses were measured through effective dose to paralyze active tension by either 50 or 95%. Protein and protein/calorie malnutrition leading to an approximate 8% body weight loss caused a depression of maximal tension developed; this depression in tension was associated with a 10-fold increase in cAMP levels. Effective doses of d-tubocurarine for twitch inhibition during malnutrition were not significantly different from controls. Sepsis at 2 weeks caused an approximate 8% body weight loss, a significant decrease in maximal tension and at least a 3- to 5-fold shift to the right in dose-response curves to d-tubocurarine. In contrast to malnutrition, cAMP levels were significantly decreased (P less than .001) in sepsis to 1/400 of controls. The altered neuromuscular function and pharmacology observed in sepsis are similar to changes observed in burn injury. Protein malnutrition common to these two states may be important in functional but not pharmacological changes at the neuromuscular junction.
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PMID:Intraperitoneal endotoxin but not protein malnutrition shifts d-tubocurarine dose-response curves in mouse gastrocnemius muscle. 254 58

The protein B of group B streptococci can bind in a nonimmune reaction to Ig of the IgG and IgM classes of various mammalian species (i.e., human, mouse, rabbit, and bovine). Protein B binding involves the Fc parts of both IgG and IgM molecules. Monoclonal or polyclonal IgG or IgM and the IgM-FC5 mu fragment of human myeloma protein combined with the protein B thereby inhibiting protein B-induced hemolysis in the CAMP reaction. The protein B/Ig complex can be dissociated with 1% Triton or guanidine-HCl (6 M). Mice infected intraperitoneally with sublethal doses of group B streptococci (GBS) and that received seven repeated intravenous injections of highly purified protein B during the first 9 h of infection developed fatal septicemia within 24 h with colony counts of up to 10(8) CFU/ml in the blood. Animals treated in the same way with either PBS or trypsinized protein B recovered. The protein B itself was not pathogenic when injected into healthy mice. Tissue sections of liver or spleen from mice infected with a lethal dose of GBS revealed the presence of protein B together with large numbers of cocci when stained by the peroxidase method using specific antibodies raised against purified protein B in the rabbit.
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PMID:Unspecific binding of group B streptococcal cocytolysin (CAMP factor) to immunoglobulins and its possible role in pathogenicity. 354 80

This is a very brief, superficial and biased discussion of the pathophysiologic changes in shock. It was designed to provide some insight into the very complex changes that occur, with particular attention to a few examples of the impaired cell metabolism, including changes in ATP, cAMP, and calcium. Although inadequate tissue perfusion through nutrietn capillaries is the main etiologic factor in most types of shock, it is not the primary problem in many patients, particularly those with early or hyperdynamic sepsis. The importantance of oxygen consumption and the possible benefits of higher hemoglobin levels are discussed to some extent because of their possible clinical application.
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PMID:The pathophysiology of shock. 736 11

We report that, in rats, the lethal consequences of high-dose endotoxin challenge are exacerbated by the intravascular administration of prostaglandin E1 but attenuated by the intravascular administration of endocytosable particles. This protection is mediated by opsonins. Nonopsonizable particles were unable to provide protection unless first pseudoopsonized with antibody directed against the CR3 (CD11b/CD18) phagocyte receptor. We show that endogenously opsonized particles can act in concert with prostaglandin E1 (putatively by elevation of neutrophil intracellular cAMP and the resultant downregulation of CR3) to completely rescue animals from the lethal late-stage sequelae of experimental endotoxemia. These data illustrate that the interaction of particles with cellular receptors can transform the overall systemic response to prostaglandin E1 from pro- to antiinflammatory. This suggests a role for multiple receptor engagement events in defining the systemic prostaglandin response and offers a rationale for developing new therapeutic modalities in the treatment of sepsis and other inflammatory diseases.
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PMID:Endogenously opsonized particles divert prostanoid action from lethal to protective in models of experimental endotoxemia. 770 30

Tumor necrosis factor-alpha (TNF-alpha), a monokine that contributes to vascular dysfunction accompanying the host response to gram-negative sepsis, has been shown to increase vascular permeability in vivo and to diminish the barrier function of cultured endothelial cell (EC) monolayers. The studies reported here indicate that a mechanism through which TNF alters EC barrier function involves a reduction in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) content, due in part to increased cyclic nucleotide phosphodiesterase (CNPDE) activities. TNF increased the diffusional transit of [3H]sorbitol, [3H]inulin, and 125I-labeled albumin across confluent bovine aortic EC monolayers. This effect of TNF was both time and dose dependent and occurred in parallel with a fall in EC cAMP. cAMP analogues, such as dibutyryl cAMP (DBcAMP), prevented TNF-induced perturbation of EC barrier function. TNF also mediated another important alteration in the EC phenotype, in that both mRNA and activity of the anticoagulant cofactor thrombomodulin were reduced after exposure of EC to TNF and were normalized by the addition of DBcAMP. EC monolayers exposed to TNF-alpha showed increased cAMP levels when exposed to 3-isobutyl-1-methylxanthine, a nonspecific CNPDE inhibitor. Ion exchange chromatography of cytosol derived from TNF-treated EC consistently showed an approximately 245% increase in phosphodiesterase (PDE) IV (high-affinity, cAMP-specific PDE) activity as identified by rolipram inhibition. PDE II activity was increased by 150% after TNF-alpha treatment of early passage EC, which was identified by cGMP-activated hydrolysis of cAMP. Western and Northern analyses, as well as activity studies, revealed that TNF treatment did not change the amount of PDE IV protein or mRNA but rather increased the specific activity of the isozyme, suggesting that a posttranslational modification had occurred. These data indicate that activation of EC CNPDE activity and decreased intracellular cAMP may represent a mechanism by which TNF increases EC permeability and promotes a procoagulant EC phenotype.
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PMID:TNF modulates endothelial properties by decreasing cAMP. 776 2

The mechanism by which PG of the E series (PGE) promote murine B lymphocyte IgE production was investigated. We previously reported that PGE, and other agents that increase intracellular cAMP, synergize with IL-4 and LPS to induce IgE and IgG1 production while inhibiting IgM and IgG3 synthesis. These data suggested that PGE may promote IL-4-induced class switching, but the mechanism by which PGE increases IgE synthesis remained obscure. We report here that 1) PGE increases (up to 14-fold) the number of splenic B cells secreting IgE, even though PGE mildly inhibits proliferation. 2) PGE acts on sorted surface IgM positive B cells, consistent with PGE acting on uncommitted B cells to promote class switching to IgE. 3) PGE synergizes with IL-4 to induce germline epsilon transcripts, demonstrating that PGE acts at the level of transcription in cells that have not yet switched to IgE. 4) In the presence of PGE, rearranged mature V(D)J epsilon mRNA transcripts can be detected earlier and at higher levels than with IL-4 and LPS alone. Taken together, these data provide strong evidence that PGE synergizes with IL-4 and LPS to direct isotype switching to the epsilon heavy chain gene in purified B lymphocytes. PGE is a potentially important in vivo immunoregulator, particularly with regard to IgE production and the genesis of allergy. In support of this hypothesis, there are numerous clinical conditions (hyper-IgE, trauma, sepsis, Hodgkin's lymphoma, arthritis) in which overproduction of PGE is coincident with elevated IgE titers.
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PMID:Prostaglandin E2 promotes B lymphocyte Ig isotype switching to IgE. 799 35


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