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)

To examine the role of systemic plasma tumor necrosis factor (TNF) in the septic response following trauma, an endotoxin (lipopolysaccharide (LPS)) challenge was administered to anesthetized mongrel pigs 72 h following either hemorrhagic shock/resuscitation or sham shock. For TNF to be considered a mediator, at least two conditions should be satisfied: a TNF increase should precede other manifestations of the septic response and the magnitude of that increase should correlate with the symptoms. Immediately following resuscitation from shock, hemodynamics were stable, but heart rate, cardiac index (CI), and systemic oxygen delivery (DO2) were elevated 20-60%, and systemic vascular resistance (SVR) was decreased 40%, relative to the preshock baseline. After 72 h, the animals were reanesthetized, reinstrumented, and all hemodynamic values were near normal in both groups. At this point, either 1.5 (shock, n = 2; sham, n = 2), 15 (shock, n = 7; sham, n = 6) or 150 (shock, n = 11; sham, n = 4) micrograms/kg of Escherichia coli LPS was administered intravenously over 30 min. Serial hemodynamic data, complete blood counts, and TNF were recorded for 3 h post-LPS. LPS evoked profound leukopenia and pulmonary hypertension within 15 min that was followed by a hyperdynamic septic response (i.e., progressive arterial desaturation, tachypnea, tachycardia, increased CI, and decreased SVR) and rise in plasma TNF at 60-90 min. In the shock group, LPS-evoked TNF changes were less than or equal to those in the sham group, even though mortality was higher after shock.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasma tumor necrosis factor and post-traumatic hyperdynamic sepsis evoked by endotoxin. 773 48

Sixteen sheep were surgically prepared for chronic study. Seven days later, Escherichia coli endotoxin (10 ng/kg/min, lipopolysaccharide (LPS) group, n = 10) or an equivalent amount of 0.9% NaCl (Control group n = 6) was administered. Between 1 and 8 h post-LPS, there was a hypodynamic state with low cardiac index (CI, LPS 5.0 +/- 0.2; sham 6.3 +/- 0.4 liters/min/m2 at 4 h). During this period, the left ventricular end-systolic pressure-diameter relationship (ESPDR), a sensitive index of myocardial contractility, was also lower (LPS 10.4 +/- 1.2; sham 17.2 +/- 0.8 mmHg/mm). Mean pulmonary arterial pressure (PAP) and pulmonary vascular resistance index (PVRI) were remarkably increased 1 h after the administration of LPS (PAP:LPS 37.5 +/- 1.9; sham 21.8 +/- 0.9 mmHg, PVRI: LPS 600 +/- 58; sham 158 +/- 23 dynes x s x cm-5 x m2). The early changes in cardiopulmonary function occurred concomitantly with an elevation in tumor necrosis factor (LPS 1221 +/- 520; sham 0 +/- 0 pg/ml) and thromboxane B2 (LPS 1382 +/- 266; baseline 82 +/- 20 pg/ml) in arterial blood. Following this first phase, the sheep presented a persistent hyperdynamic state characterized by a significant increase in CI. The ESPDR continued to fall. By 24 h post-LPS the CI was 10.1 +/- 0.5 liters/min/m2 (sham, 6.3 +/- 0.3) but the ESPDR had fallen to 8.2 +/- 2.3 mmHg/mm (sham 16.0 +/- 3.0). The pulmonary hypertension was maintained for the duration of the LPS infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Left ventricular dysfunction and acute lung injury induced by continuous administration of endotoxin in sheep. 773 64

Endothelin-1 (ET-1) is known to be involved in a variety of pathophysiologic conditions, especially of the pulmonary vasculature. The aim of this study was to investigate physiologic mediators potentially involved in the pathogenesis of pulmonary hypertension, for their effects on ET-1 gene expression at both the transcriptional and translational level. Rat microvascular and pulmonary artery endothelial cells grown in culture were exposed to vasoactive mediators (thrombin or an anoxic gas mixture) and inflammatory mediators (lipopolysaccharide, interleukin 1 alpha, interleukin 1 beta, or tumor necrosis factor alpha) for various time periods. The change in prepro-ET-1 (ppET-1) mRNA levels in these cells in response to stimuli was a time-dependent phenomenon. The inflammatory mediators caused an acute rise in ppET-1 mRNA levels whereby peak induction occurred after 1 h with a rapid decline to control levels by 4 h. The vasoactive mediators elicited a more sustained response whereby a significant elevation in ppET-1 mRNA expression occurred quickly and remained elevated through 4 h. The pattern of induction was more rapid for thrombin than for anoxic gas exposure. Radioimmunoassay analysis demonstrated a similar response for thrombin and the inflammatory mediators in ET-1 mature peptide release, whereas the effect of anoxic gas exposure was divergent. Significant elevations were noted after 6 h for thrombin as well as each of the inflammatory mediators except IL-1 alpha. In response to the anoxic gas exposure, however, a significant rise in ET-1 peptide release was not evident until after 24 h. To determine the level at which ppET-1 mRNA induction is regulated, cells were cotreated with each of the stimuli and actinomycin D or cycloheximide. Results indicate that the induction of ppET-1 mRNA levels is likely due to de novo transcription, as well as mRNA stabilization. In summary, inflammatory and vasoactive agents are important regulators of ET-1 gene expression in rat pulmonary endothelial cells; most important, we observed a differential response at the mRNA or peptide level depending on the mediator involved.
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PMID:Effects of vasoactive and inflammatory mediators on endothelin-1 expression in pulmonary endothelial cells. 774 14

Effects of amrinone (AMR), a phosphodiesterase inhibitor, alone and in combination with dobutamine (DOB), on hemodynamics and O2 delivery were studied during porcine endotoxemia. Pentobarbital-anesthetized pigs were randomly administered either Escherichia coli lipopolysaccharide (endotoxin) or equivolumetric .9% NaCl (control) as a continuous infusion for 4 h. From 2 to 4 h (T = 120-240 min) of endotoxin infusion, pigs were randomly administered one of the following treatments; AMR infusion (40 micrograms/kg/min) (AMRlow); DOB (10 micrograms/kg/min) (DOB); AMR infusion (40 micrograms/kg/min) + DOB (AMRlow+DOB); AMR bolus (.75 mg/kg) followed by AMR infusion (40 micrograms/kg/min) (AMRhigh); or AMR bolus (.75 mg/kg) followed by infusion (40 micrograms/kg/min) + DOB (AMRhigh+DOB). Myocardial samples were obtained at the end of the experiment and flash-frozen for beta-adrenergic receptor analysis. Endotoxin significantly (p < .05) decreased cardiac index, right ventricular ejection fraction, stroke volume index, maximum rate of rise of left ventricular pressure (dP/dtmax), mean arterial pressure, and O2 delivery, and increased pulmonary vascular resistance and mean pulmonary arterial pressure (p < .05). AMRlow+DOB significantly (p < .05) increased cardiac index, dP/dtmax, right ventricular ejection fraction, stroke volume index, O2 delivery and consumption, and decreased mean pulmonary arterial pressure, pulmonary vascular resistance, mean arterial pressure, and systemic vascular resistance. beta-Adrenergic receptor density (Bmax) and binding equilibrium dissociation constant (KD) for [3H]dihydroalprenolol were not affected by endotoxin or any treatment (p < .05). Endotoxin-induced hemodynamic deterioration and decreased O2 delivery was attenuated by AMRlow+DOB. Potential applications of this combination may exist in treatment of septic patients with inadequate myocardial performance and reduction in O2 delivery complicated by pulmonary hypertension.
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PMID:Amrinone combined with dobutamine improves hemodynamics and oxygen delivery without down-regulation of cardiac beta-adrenergic receptor density in porcine endotoxemia. 777 3

Both tumor necrosis factor (TNF) and platelet-activating factor (PAF) are released during sepsis and are important mediators of septic lung injury. I investigated the interactions of TNF and PAF on vasoactive responses in the pulmonary circulation. In isolated rat lungs perfused with a cell- and plasma-free physiological salt solution, PAF (0.01- and 0.1-micrograms boluses) caused transient dose-dependent pulmonary arterial and venous constrictions. In vivo pretreatment of the rats with TNF (0.02 or 0.2 mg/kg i.v.) 1 h before lung isolation increased lung myeloperoxidase activity and markedly enhanced PAF-induced pulmonary vasoconstriction without affecting the pressor responses to angiotensin II or hypoxia. In contrast, pretreatment with lipopolysaccharide (10 mg/kg), which increased lung myeloperoxidase to the same extent as TNF, caused only a modest enhancement of PAF-induced vasoconstriction associated with reduced pressor responses to angiotensin II and hypoxia. Ex vivo perfusion of isolated lungs with TNF for 1 h did not affect PAF vasoconstriction. The TNF-induced potentiation of PAF vasoconstriction was not altered by depletion of circulating neutrophils with vinblastine but was blocked by Dazmegrel, a thromboxane synthase inhibitor. Thus, TNF potentiates PAF-induced pulmonary vasoconstriction by an in vivo mechanism that is neutrophil independent but thromboxane dependent. This TNF-PAF interaction likely contributes to the development of pulmonary hypertension during sepsis.
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PMID:TNF potentiates PAF-induced pulmonary vasoconstriction in the rat: role of neutrophils and thromboxane A2. 789 27

The triazolodiazepine WEB 2086, a specific platelet activating factor (PAF) receptor antagonist, has previously been shown to prevent pulmonary hypertension, hypoxia, and bronchoconstriction when given before bacterial lipopolysaccharide (LPS). The aim of the present study was to examine whether WEB 2086 reduced these changes even when given after the onset of LPS-induced shock. In a randomized trial LPS was given intravenously (i.v.) in a dose of 1 microgram/kg/h for 8 hours to anesthetized, ventilated pigs. Ten animals received LPS and WEB 2086, 10 mg/kg/h i.v. for 6.5 hours, beginning 1.5 hours after LPS. Ten control animals received LPS and saline. During treatment with WEB 2086, pulmonary hypertension was significantly attenuated compared with the findings in the control group. Gas exchange, airway pressure, extravascular lung water levels, intrapulmonary shunt, and cathepsin B levels in plasma showed a trend toward improvement but the group differences were not statistically significant. These data indicate that the PAF antagonist WEB 2086 can partially block pulmonary dysfunction and enzyme release from inflammatory cells when given during ongoing LPS shock in pigs, and that PAF may be an important mediator of the cardiopulmonary changes seen in septic shock.
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PMID:Delayed treatment with platelet activating factor receptor antagonist web 2086 attenuates pulmonary dysfunction in porcine endotoxin shock. 796 71

Serum contains proteins that may produce lung injury directly by affecting endothelial cells and indirectly by modulating the effects of endotoxin (lipopolysaccharide). We studied the effects of 10% serum, 10% plasma, and 10% plasma plus 2 micrograms/mL lipopolysaccharide on pulmonary hypertension and vascular permeability in the isolated perfused rabbit lung. Control lungs perfused with Krebs-Henseleit buffer containing 3% albumin for 2 h had stable pulmonary vascular pressures and permeability (measured by the capillary filtration coefficient). Serum produced pulmonary hypertension and increased pulmonary vascular permeability. In contrast, plasma, with and without lipopolysaccharide, did not alter pulmonary vascular pressures or permeability. Pretreatment with the cyclooxygenase inhibitor indomethacin prior to the addition of serum prevented the serum-induced increase in pulmonary vascular pressures and permeability. We conclude that the deleterious effects of serum are not due to plasma proteins per se, but instead are related to activation of the coagulation cascade during preparation of the serum. The deleterious effects of serum appear to be mediated by cyclooxygenase metabolites of arachidonic acid. Finally, endotoxin, even with the addition of plasma, does not directly produce lung injury.
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PMID:Serum but not plasma produces injury in the perfused rabbit lung. 801 Apr 52

The major pore-forming exotoxin of Staphylococcus aureus, staphylococcal alpha-toxin, causes thromboxane-mediated pulmonary hypertension and prostanoid-independent protracted vascular leakage in perfused rabbit lungs. We asked whether lung responsiveness to the staphylococcal agent would be altered by a preceding period of endotoxin priming. Isolated rabbit lungs were perfused with Krebs-Henseleit buffer in the presence or absence of 100 ng/ml Salmonella abortus equii endotoxin for up to 5 h. The lipopolysaccharide exposure evoked the release of large quantities of tumor necrosis factor into the vascular and alveolar spaces but did not significantly alter pulmonary artery pressure, organ weight, or the repeatedly assessed capillary filtration coefficient (Kfc). Two and 4 h after endotoxin administration, alpha-toxin (10 to 30 ng/ml) was bolus-injected into the pulmonary artery. Toxin-evoked prostanoid generation (TxB2, 6-keto-PGF1 alpha) and pressor responses were markedly accelerated and enhanced in endotoxin-primed lungs, both for the 2 h and the 4 h priming period. No significant influence of endotoxin was noted when applied simultaneously with alpha-toxin. Cyclooxygenase inhibition suppressed the alpha-toxin-evoked pressure rise in both endotoxin-primed and nonprimed lungs. Endotoxin priming did not influence the alpha-toxin-induced protracted increase in Kfc values, assessed in the presence of cyclooxygenase inhibition. We conclude that endotoxin primes rabbit lungs for enhanced prostanoid generation and pulmonary hypertension in response to S. aureus alpha-toxin. Such cooperativity of endotoxin priming and exotoxin triggering may be relevant in critically ill patients suffering from both endotoxemia and gram-positive sepsis.
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PMID:Endotoxin primes perfused rabbit lungs for enhanced vasoconstrictor response to staphylococcal alpha-toxin. 823 51

The cross-protective effects of a murine immunoglobulin M monoclonal antilipid A antibody (E5 MAb) were tested by challenging awake sheep with mixtures of in vitro incubated E5 MAb (0.02 mg/kg) with lipopolysaccharide (LPS, 0.02 micrograms/kg) derived from Escherichia coli O111:B4, E. coli O55:B5, or Serratia marcescens. Intravenous infusion of these LPS preparations without antibody into awake sheep produced a similar pattern of fever, leukopenia, plasma thromboxane B2 (TxB2) release, and acute pulmonary vasoconstriction with pulmonary hypertension. The addition of MAb E5 to LPS from E. coli O111:B4 reduced these responses to the LPS in a fashion comparable to that achieved with an MAb specific to the E. coli O111:B4 O-side chain. Incubation of LPS derived from E. coli O55:B5 with the E5 MAb only slightly diminished acute pulmonary hypertension, the delayed temperature increase, and the degree of leukopenia (all P = NS) but reduced the mean peak TxB2 at 60 min (P < 0.05) compared with a control infusion of E. coli O55:B5 LPS. We were unable to demonstrate any protective effects on the pulmonary circulation from incubating E5 with LPS derived from S. marcescens. Preincubation of B55 MAb (a murine immunoglobulin M MAb directed against a human milk fat globulin), the control antibody, with LPS from E. coli 0111:B4 decreased the mean peak TxB2 but had no effect on the other parameters. We conclude that incubating E5 with LPS protects the pulmonary circulation of sheep from challenge with LPS derived from the parent E. coli strain. There were trends toward protection by E5 against LPS from 055:B5 E. coli, but these did not reach statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protective effects of E5, an antiendotoxin monoclonal antibody, in the ovine pulmonary circulation. 837 69

Nitric oxide (10 ppm) inhaled by pigs before or during endotoxin shock induced by an infusion of E. coli lipopolysaccharide. Nitric oxide inhalation selectively attenuated pulmonary hypertension during endotoxin infusion without influencing mean arterial blood pressure and cardiac output. Upon cessation of nitric oxide inhalation, pulmonary artery pressure rapidly increased to levels seen in endotoxin-treated controls. The oxygenation and pH of arterial blood were significantly higher in the animals receiving nitric oxide. A marked increase in arterial plasma noradrenaline and neuropeptide Y was seen in endotoxin-treated control pigs while in the nitric oxide-treated pigs this increase was markedly reduced. The increase in arterial plasma endothelin-1 was not influenced by nitric oxide inhalation. Infusion of L-arginine (substrate for nitric oxide synthesis) also attenuated the pulmonary hypertension but was not selective for the pulmonary vasculature. L-Nitro-arginine (a nitric oxide synthesis inhibitor) initiated a rapid but brief elevation of arterial blood pressure and of pulmonary artery pressure as well as a reduction in cardiac output. Nitric oxide inhalation selectively reduces pulmonary hypertension in porcine endotoxin shock and improves arterial oxygenation and pH with a marked attenuation of sympathetic activation.
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PMID:Nitric oxide inhalation attenuates pulmonary hypertension and improves gas exchange in endotoxin shock. 847 50


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