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)

Inhibitors of cyclic nucleotide phosphodiesterases are known to suppress lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-alpha) production in vitro in human monocytes. The most potent of these have selectivity for type IV PDEs, suggesting that this class of PDE is the major type involved in the regulation of human TNF-alpha production. Using compounds of two distinct chemical structural classes, a quinazolinedione (CP-77059) and a 4 arylpyrrolidinone (rolipram), we show here that PDE-IV-specific inhibitors are also potent in suppressing LPS-induced TNF-alpha production in vitro in sodium periodate-elicited murine macrophages (IC50s of 1 and 33, respectively). We then report the in vivo anti-inflammatory effect of PDE-IV inhibition in five murine models of inflammation: (i) elevation of serum TNF-alpha induced by a sublethal LPS injection; (ii) LPS-induced endotoxic shock; (iii) LPS/galactosamine-induced endotoxic shock; (iv) carrageenan-induced paw oedema; and (v) adjuvant arthritis. Following a sublethal (5 micrograms/mouse) injection of LPS, serum TNF-alpha levels in mice peaked sharply, reaching concentrations of 3-12 ng/ml 90 min after injection. In this sublethal LPS assay, CP-77059 was about 30 times more potent than rolipram, with a minimum effective dose of 0.1 mg/kg versus 3 mg/kg for rolipram. This rank order is in keeping with the relative in vitro IC50s for CP-77059 and rolipram, as well as their relative Ki against the human PDE-IV enzyme (46 nM and 220 nM, respectively). In LPS-induced endotoxic shock, rolipram and CP-77059 at relatively high doses of 30 and 10 mg/kg, respectively, significantly reduced serum TNF-alpha levels, and also inhibited mortality 66%. In the LPS/galactosamine shock model, in which mice are rendered exquisitely sensitive to LPS by co-injection with galactosamine, only 0.1 microgram of LPS/mouse is necessary for serum TNF-alpha elevation and death. Both rolipram and the CP-77059 caused dose-dependent reduction of serum TNF-alpha and lethality. In the carrageenan-induced paw oedema model, in which there is a pronounced local TNF-alpha response (without a serum TNF-alpha elevation), rolipram significantly inhibited paw swelling as well as localized TNF-alpha levels in the paw. In the adjuvant arthritis model, a chronic model of inflammation also possessing localized TNF-alpha elevation in the inflamed paw, rolipram and CP-77059 suppressed ankle swelling and radiological evidence of joint damage. These data are consistent with a major role for PDE-IV in regulation of TNF-alpha production and inflammatory responses in murine systems.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation. 769 10

1. Hypotension and vascular hyporesponsiveness to vasoconstrictors are observed during endotoxic shock, and are associated with increased production of nitric oxide in the vascular wall. Disseminated intravascular coagulation is another feature of septicaemia. We hypothesized that thrombin generated during disseminated intravascular coagulation might modulate the changes in vascular tone induced by endotoxin. 2. Incubation of rat aortic rings for 4 h with alpha-thrombin (0.003-3.0 NIH units/ml) did not change their reactivity to noradrenaline. Incubation for 4 h with lipopolysaccharide increased the EC50 for noradrenaline, whereas co-incubation of thrombin (0.5 NIH units/ml) with lipopolysaccharide did not alter this hyporeactivity to noradrenaline. 3. In vivo in rats, lipopolysaccharide caused early (1 h) and late (4-6 h) hyporeactivity to noradrenaline. In rats infused with lipopolysaccharide and heparin (1 U min-1 kg-1, 0.4 ml/h) or hirudin (2.2 mg ml-1 kg-1, 0.8 ml/h), vasopressor responses to noradrenaline were not different from those after infusion of lipopolysaccharide alone. Aortic rings taken from rats receiving both anticoagulant treatment and lipopolysaccharide had the same sensitivity to noradrenaline as those obtained from rats receiving lipopolysaccharide alone. 4. Our results suggest that, in vivo, disseminated intravascular coagulation does not modify the early and late effects of lipopolysaccharide on arterial pressure and that, in vitro, thrombin neither induces hyporeactivity to noradrenaline nor modifies lipopolysaccharide-induced hyporeactivity. We propose that thrombin generated during disseminated intravascular coagulation in rats does not play a major role in the alterations of vascular tone observed during endotoxic shock.
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PMID:Thrombin does not alter vascular hyporeactivity in models of endotoxin-induced septic shock in rats. 772 Mar 38

Endotoxin (lipopolysaccharide, LPS) can induce shock, multiple organ failure, and death. A recombinant N-terminal fragment of bactericidal/permeability increasing protein, rBPI23, binds with high affinity to gram-negative bacterial LPS and neutralizes its biological activity. We sought to determine the effect of rBPI23 on LPS-induced respiratory dysfunction and cardiovascular depression in conscious rabbits. Rabbits were injected with Escherichia coli O113 LPS (6 micrograms/kg) and treated with rBPI23 (2 mg/kg), vehicle, or control protein after recovery from surgery performed to implant catheters for hemodynamic assessments and intravenous injections. LPS challenge caused respiratory dysfunction including tachypnea, significant decreases in arterial O2 tension (PO2), arterial oxygen content, and an increase in alveolar-arterial O2 gradient (A-aDO2). LPS administration also resulted in profound and prolonged decreases in mean arterial blood pressure and cardiac index. Treatment with rBPI23 prevented LPS-induced respiratory dysfunction and significantly ameliorated the cardiovascular depression. 5 of 16 LPS-challenged animals died of respiratory failure and acidosis, whereas none died in the rBPI23 treated group (p = .11). The results demonstrate that rBPI23 protects animals against LPS-induced cardiopulmonary depression in endotoxic shock.
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PMID:Protective effects of a recombinant N-terminal fragment of bactericidal/permeability increasing protein on endotoxic shock in conscious rabbits. 774 57

The effect of CV-3988, a platelet activating factor antagonist, in the treatment of endotoxic shock was evaluated from the changes in plasma 6-keto-PGF1 alpha and thromboxane B2 concentrations. The animals consisted of 10 beagle dogs anesthetized with pentobarbital sodium and divided into a treatment group (n = 5) and a control group (n = 5). Endotoxic shock was experimentally induced in both groups by intravenous administration of endotoxin (lipopolysaccharide, 3 mg/kg). The treatment group was intravenously given 10 mg/kg of CV-3988 for 10 min from immediately after endotoxin. Mean aortic pressure, cardiac output and urine volume were remarkably decreased after the administration of endotoxin to both groups. These parameters were higher after the administration of CV-3988, in the treatment group than in the control group. Furthermore, the increase in plasma 6-keto-PGF1 alpha and thromboxane B2 concentrations was significantly inhibited. These results suggest the effectiveness of CV-3988 in the treatment of endotoxic shock.
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PMID:Effect of platelet activating factor antagonist (CV-3988) on 6-keto-PGF1 alpha and thromboxane B2 in dogs with experimental endotoxin-induced shock. 775 31

Multisystem organ failure (MSOF) is the major cause of late death following trauma. The gut is hypothesized to be the source of an ongoing systemic inflammatory response that drives MSOF. It has also been suggested that while a single physiologic insult might not reliably cause MSOF, the addition of a delayed second stress will. This is known as the "two-hit" theory. The purpose of this study was to investigate the two-hit theory by observing the hemodynamic and bacteriologic response to a second stress in a subacute pig model of hemorrhagic and endotoxic shock. Swine (n = 18, 30-40 kg) were fed an antibiotic-free diet for 14 days. During instrumentation and experimentation on days 1 and 3, all animals were anesthetized (ketamine, isofluorane). On day 1, all animals had placement of central venous and arterial catheters, a portal venous catheter, and superior mesenteric artery flow probe. Group E (n = 6) underwent instrumentation on day 1, then infusion of endotoxin (25 mcg/kg E. coli lipopolysaccharide) on day 3. Group HE (n = 7) underwent instrumentation then hemorrhagic shock (mean arterial pressure = 40 mm Hg for 4 hours) on day 1, then infusion of endotoxin on day 3. Group H (n = 5) were instrumented and hemorrhaged on day 1, and underwent anesthesia only on Day 3. Between periods of anesthesia the animals were allowed food and water ad lib and systemic blood was sampled for culture every 12 hours. On day 5, the animals were euthanized prior to organ sampling for bacterial culture. One animal from group HE died during endotoxic shock on day 3.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemodynamic changes and gut barrier function in sequential hemorrhagic and endotoxic shock. 776 Mar 96

Nitric oxide (NO) synthesis was measured in the liver, lung, spleen and kidney of lipopolysaccharide-treated male rats using the nitric oxide spin trap, iron (II)-diethyldithiocarbamate (FeDETC2). Nitric oxide formation in vivo was determined by the increase in intensity of the characteristic triplet hyperfine EPR spectrum of [NO-FeDETC2]. Intravenous bovine liver arginase, at a dose which completely depleted circulating arginine, significantly reduced the formation of nitric oxide in these tissues. The general decrease in NO levels was confirmed by the decrease in plasma nitrite levels. These results directly demonstrate that NO formation in endotoxic shock depends on extracellular arginine; depletion of plasma arginine may be a useful therapeutic strategy.
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PMID:L-arginine depletion by arginase reduces nitric oxide production in endotoxic shock: an electron paramagnetic resonance study. 778 29

Elevated tumor necrosis factor (TNF) levels have been reported in various models of acute and chronic inflammation and used by many investigators to determine the stage of disease and effectiveness of treatment. Because of the documented involvement of TNF in the mechanism of septic shock, experiments were done to determine whether serum TNF levels paralleled the pathology in endotoxic shock and other models of inflammation. When mice received an intraperitoneal injection of lipopolysaccharide, serum TNF levels increased dramatically, peaking 90 minutes after injection. In a dose-response experiment with lipopolysaccharide alone, we found no correlation between serum levels of TNF and survival rate of mice. All three lipopolysaccharide concentrations resulted in comparable elevations of serum TNF, yet only in the high-dose group did the animals die. In a second model of endotoxic shock, TNF-alpha levels in serum were again compared with the survival rate of mice receiving lipopolysaccharide plus galactosamine. As in the first model, we found no relationship between the level of TNF in mouse serum and mouse survival rate. The two lowest concentrations of lipopolysaccharide/galactosamine induced identically low levels of serum TNF, yet in one group all of the animals survived and in the other all died. Discrepancies between serum TNF level and mortality rate were also seen in drug treatment experiments. GI 147404X, a standard phosphodiesterase type IV inhibitor, inhibited lipopolysaccharide/galactosamine-induced elevation of serum TNF by 90% at doses of 1 and 10 mg/kg. However, the high dose resulted in 66% protection while the low dose afforded no protection.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evaluation of the significance of elevated levels of systemic and localized tumor necrosis factor in different animal models of inflammation. 779 95

The major objective of the present study was to determine the effects of a partial structure of the lipid A moiety of gram-negative lipopolysaccharide, monophosphoryl lipid A (MLA), on endotoxin-induced mortality and disseminated intravascular coagulation (DIC) in rats. A second objective was to examine the role of polymorphonuclear neutrophil invasion to visceral organs, including lung, liver, heart, and kidney in the pathogenesis of the compromised multiorgan function which occurs in endotoxic shock. Finally, a third aim was to determine if the potential protective effects of MLA might be mediated via inhibiting neutrophil invasion to various visceral organs. Male Sprague-Dawley rats (220-260 g) were fasted over night and used the following day. In control rats, endotoxin (S. abortus equi LPS, 15 mg/kg, i.v.) produced a 89% mortality at 48 hr following its administration, and gross pathological and laboratory signs of DIC at 3 hr after injection. The latter included increased serum fibrin(ogen) degradation products (FDP, 24.00 +/- 7.81 vs. 0 micrograms/ml, P < .05), prothrombin time (PT, 16.20 +/- 1.12 vs. 13.03 +/- 0.20 sec, P < .05), and activated partial thromboplastin time (APTT, 32.70 +/- 3.83 vs. 20.11 +/- 0.60 sec, P < .05), and decreased plasma fibrinogen (233.2 +/- 41.6 vs. 406.3 +/- 23.2 mg/dl, P < .05) as well as evidence of gross visceral hemorrhage. Pretreatment with MLA (5 mg/kg) for 24 hr produced a marked reduction in endotoxin-induced mortality at 48 hr (0% versus 89% in controls) and inhibited all of the manifestations of DIC produced by endotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monophosphoryl lipid A protects against endotoxic shock via inhibiting neutrophil infiltration and preventing disseminated intravascular coagulation. 785 Sep 30

IL-1 beta-converting enzyme (ICE) cleaves pro-IL-1 beta to generate mature IL-1 beta. ICE is homologous to other proteins that have been implicated in apoptosis, including CED-3 and Nedd-2/lch-1. We generated ICE-deficient mice and observed that they are overtly normal but have a major defect in the production of mature IL-1 beta after stimulation with lipopolysaccharide. IL-1 alpha production is also impaired. ICE-deficient mice are resistant to endotoxic shock. Thymocytes and macrophages from the ICE-deficient animals undergo apoptosis normally. ICE therefore plays a dominant role in the generation of mature IL-1 beta, a previously unsuspected role in production of IL-1 alpha, but has no autonomous function in apoptosis.
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PMID:Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. 785 82

Elevation of intracellular cAMP levels has been shown previously to inhibit cytokine secretion by various cell types in vitro. Since salmeterol is a beta 2-agonist which activates adenylate cyclase, its ability to inhibit cytokine production was evaluated. Though salmeterol, and the related drug albuterol, did not inhibit IL-1 beta production in vitro, both drugs did inhibit tumour necrosis factor-alpha (TNF-alpha) secretion by lipopolysaccharide (LPS)-activated THP-1 cells with similar IC50s of approximately 0.1 microM. This inhibition was effectively reversed by the beta 2-antagonist oxprenolol, indicating that the inhibition was mediated through the beta 2-adrenergic receptor. A strikingly different reactivity profile was seen with T cells. Salmeterol was able to inhibit the activation of both mouse and human T cells, as measured by proliferation and IL-2 secretion in response to anti-CD3 antibody, whereas albuterol was completely inactive in these assays. This T cell inhibition by salmeterol was about 10-fold less potent than that for TNF-alpha production, and was not reversed by a beta 2-antagonist, indicating that a different mechanism was involved in the effect of salmeterol on T cells. Paralleling the TNF-alpha inhibitory activity in vitro, oral dosing of salmeterol and albuterol inhibited LPS-induced increase in murine serum TNF level in vivo, with ED50s of approximately 0.1 mg/kg. This inhibition could be abrogated by dosing orally with the beta-blocker propranolol. The long-acting pharmacological profile of salmeterol was apparent in that it maintained its efficacy for 3 h, while albuterol had a much shorter duration of action. Salmeterol also had some protective effects in the galactosamine/LPS model of endotoxic shock, which is dependent upon TNF-alpha production. Though salmeterol inhibited serum TNF-alpha levels by up to 94% in this assay, it protected less than 50% of the animals from the lethal effects of the LPS/galactosamine mixture. This observation suggests that functional levels of TNF-alpha localized in tissues may not be accurately reflected by serum levels.
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PMID:Anti-inflammatory activity of salmeterol: down-regulation of cytokine production. 788 70


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