UMLS:C0027947 - FACTA Search

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Query: UMLS:C0027947 (neutropenia)
17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A reconstituted lipoprotein, containing human apolipoprotein A-I and phosphatidylcholine (1:200, molar ratio), referred to as ApoLipo, was used prophylactically in an endotoxin shock model in anesthetized rabbits. ApoLipo was administered at a dose of 75 mg protein/kg body weight 15 min before the beginning of a slow, continuous lipopolysaccharide (LPS, endotoxin) infusion (4.17 micrograms LPS/kg/hr). During the 6 hr LPS infusion, the Control-LPS group manifested a marked increase in serum tumor necrosis factor (TNF, peak value 7.82 [2.7-11.2] ng/ml at 1 hr), and many of the pathophysiologic sequelae of endotoxin shock, including hypotension (MAP: 59 +/- 7 mmHg) and metabolic acidosis (BE: -9.9 +/- 2.7) at 3 hr, and a severe neutropenia developed rapidly (PMN count: 5 +/- 3% of baseline at 30 min). In the ApoLipo treated group, serum TNF levels did not rise during the course of LPS infusion (0.1 [0.06-0.64] ng/ml at 1 hr). Hypotension (77 +/- 2 mmHg) and acidosis (-2.7 +/- 0.4) were also significantly attenuated, and the appearance of leukopenia was delayed by 1 hr (110 +/- 12% at 30 min, but 9 +/- 2% at 2 hr). Endotoxemia in the ApoLipo treated group was reduced in comparison to controls, albeit nonsignificantly. The infusion of the same dose of phosphatidylcholine without apoA-I was significantly less efficacious.
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PMID:A reconstituted, apolipoprotein A-I containing lipoprotein reduces tumor necrosis factor release and attenuates shock in endotoxemic rabbits. 832 86

The purpose of this study was to characterize the role of tumour necrosis factor (TNF) and neutrophils (PMN) in the pathogenesis of pulmonary oedema induced by endotoxin (lipopolysaccharide (LPS)). Intraperitoneal administration to BALB/c mice of 0.6-1 mg of LPS caused pulmonary oedema and lethality. This was associated with production of TNF in serum and bronchoalveolar lavage fluid and with accumulation of PMN in the lung. In this experimental model, we could block TNF production by different means: pretreatment 30 min before LPS with 4 mg/kg of i.p. chlorpromazine (CPZ), 3 mg/kg of i.p. dexamethasone (DEX), 1 g/kg p.o. of N-acetylcysteine (NAC, an antioxidant precursor of glutathione), or an anti-TNF MoAb. CPZ, DEX and anti-TNF completely prevented LPS lethality but not pulmonary oedema or pulmonary PMN infiltration, indicating that: (i) lung oedema is not the main cause of death after LPS; and (ii) lung oedema induced by LPS is not mediated by TNF. Pretreatment with NAC not only inhibited TNF production but also protected against LPS-induced pulmonary oedema, indicating that reactive oxygen intermediates are implicated. NAC also blocked TNF production in blood and in bronchoalveolar lavage. We also tested the effect of PMN depletion induced with cyclophosphamide (CP) or 5-fluorouracil (5-FU). While no pulmonary PMN infiltrate was observed in PMN-depleted mice, neutropenia did not prevent LPS lethality or oedema, indicating PMN do not play an important role in the toxic effects of LPS in this experimental model.
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PMID:Role of tumour necrosis factor and reactive oxygen intermediates in lipopolysaccharide-induced pulmonary oedema and lethality. 844 68

To determine actions of acute intoxication on pathophysiologic responses to trauma, anesthetized and ventilated mongrel pigs received a 20% solution of ethanol (EtOH) by an intravenous (IV group; 2 g/kg, n = 8) or an oral (PO group; 3 g/kg, n = 12 x 60 minutes) route of administration, or the lactated Ringer's vehicle (LR group; n = 12). After 60 minutes, all were subjected to soft tissue injury and 30 to 35% hemorrhage, 60-minute shock, and then resuscitation, with shed blood plus supplemental LR. After 3 days, host defense was challenged with Escherichia coli lipopolysaccharide (LPS); (1 microgram/kg x 30-minutes IV). The supplemental resuscitation was identical (50-53 mL/kg/hours), but posttraumatic acidosis was observed in the IV group and the PO group (base deficit = 4.4 +/- 1.3 and 5.5 +/- 0.9 mEq/L) and not in the LR group. After 3 days, the acid-base equilibrium was restored, but a difference in host defense was unmasked by LPS. In the LR group, LPS-evoked pulmonary vasoconstriction was followed by decreased compliance and ventilation-perfusion mismatch, which was associated at 3 to 5 hours with a base deficit, reduced SVO2, and reduced PO2 (-0.5 +/- 0.2 mEq/L, 46 +/- 1%, 127 +/- 1 mm Hg). These changes were blunted in the PO group (2.0 +/- 0.1 mEq/L, 56 +/- 1%, 183 +/- 4 mm Hg) and potentiated in the IV group (-4.3 +/- 0.5 mEq/L, 40 +/- 2%, 60 +/- 2 mm Hg), even though more fluid was required to maintain systemic arterial and cardiac filling pressures following LPS administration in the IV (40 +/- 6 mL/kg/ hours) versus the LR or PO groups (31 +/- 5 or 23 +/- 3). The PO versus LR differences could not be attributed to enteral nutrition because an isocaloric solution of 50% dextrose had no effect versus LR solution. EtOH caused neutropenia following trauma, relative to LR solution, but the IV versus PO differences could not be discriminated on the basis of neutrophil or lymphocytes counts, nor CD18 receptor expression, nor renal or hepatic dysfunction. However, T4 lymphocytes and cortisol, a nonspecific index of inflammation, were higher for at least 24 hours after trauma with IV, relative to PO or LR. Blood EtOH was similar with IV or PO during resuscitation (100-120 mg/dL), but the kinetics were different prior to trauma. With PO, blood EtOH slowly accumulated to a steady state plateau, the level of which was higher with no anesthesia or no trauma. With IV, blood EtOH peaked at 275 mg/dL and then exponentially declined with a rate that was not influenced to a major extent by trauma or by anesthesia. Therefore: 1) EtOH absorption is impaired during trauma (in part because of reduced gut blood flow); 2) acute EtOH intoxication at the time of trauma altered neutrophils, plasma cortisol, and T4 lymphocytes during recovery and host defense to a superimposed LPS challenge. The apparently favorable effect of PO versus IV EtOH on the response to endotoxemia after trauma probably reflects differences in the kinetics of blood EtOH in the interval before reperfusion but a "first pass" effect (metabolism in the gut or liver) might also explain the data.
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PMID:Acute ethanol intoxication and endotoxemia after trauma. 867 25

Polymorphonuclear neutrophils (PMNs) may contribute to organ injury in both hemorrhagic and endotoxic shock. Both models of shock exhibit a "flight of the leukocytes," but the mechanisms for entrapment of leukocytes in the microcirculation differ. The objective of this study was to investigate lipopolysaccharide (LPS)-induced shock and hemorrhagic shock with similar survival rates, in terms of circulating PMNs, activated circulating PMNs, plasma tumor necrosis factor (TNF) activity, and PMN adhesion. In the LPS protocol, rats received 6.5 mg/kg E. coli LPS i.v., which resulted in 50% survival. In the hemorrhagic shock protocol, rats were maintained for 3 h at 40 mm Hg mean arterial pressure, and survival during a 24-h observation period was 40%. LPS injection and hemorrhage caused rapid neutropenia in survivors and nonsurvivors. Low circulating PMN counts persisted during hypotension in the hemorrhagic protocol and among nonsurvivors in the LPS protocol, but in both protocols a tendency toward significantly higher circulating PMN counts in survivors compared with nonsurvivors was found. In both protocols, survivors had significantly lower fractions of circulating activated PMNs and lower adhesion of circulating PMNs to nylon fibers. In the LPS protocol, higher plasma TNF activity was found in nonsurvivors than in survivors, but no TNF activity in plasma could be found throughout the hemorrhagic protocol. These results indicate that nonsurvivors in both shock models exhibit higher levels of PMN activation. No correlation was detected between PMN activation and plasma TNF activity to suggest that TNF serves as the primary mediator of circulating PMN activation.
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PMID:Neutrophil activation, tumor necrosis factor, and survival after endotoxic and hemorrhagic shock. 869 57

B464 is a novel synthetic analog of lipid A, a toxic component of endotoxin (LPS; lipopolysaccharide). We investigated the effects of B464 on both LPS-induced cellular responses in vitro and acute lung injury in vivo. In the in vitro study, B464 inhibited tumor necrosis factor-alpha (TNF-alpha) production from human monocytes, priming and stiffening of neutrophils, and expression of adhesion molecules on endothelial cells induced by LPS. We then studied the effects of B464 pretreatment on acute lung injury elicited by intravenous LPS administration in vivo. Guinea pigs were divided into saline control, B464 alone, LPS alone, and LPS + B464 groups. Animals were observed for 4 h after LPS administration, and lung injury was evaluated by extravascular lung water, 125I-albumin leakage in lung tissue, and lung neutrophil accumulation. In the LPS alone group, rapid and sustained peripheral neutropenia (p < 0.001 versus saline at 15 min and at 1, 2, and 4 h), an increased plasma TNF-alpha concentration (p < 0.005 at 1 h), and increases in lung injury parameters (p < 0.05) were observed. In the LPS + B464 group, no changes were observed in either plasma TNF-alpha or lung injury parameters. Transient peripheral neutropenia and subsequent rapid recovery (p > 0.05, p < 0.001, p < 0.01, and p > 0.05 at 15 min and 1, 2, and 4 h, respectively) were observed in the LPS + B464 group. These in vivo data, together with in vitro evidence of suppressed cellular responses, suggest that B464 (1) inhibits neutrophil accumulation in lung tissue, and (2) attenuates the development of acute lung injury by blocking the activation of neutrophils and mononuclear cells as well as the interaction between neutrophils and endothelial cells.
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PMID:Protective effect of B464, a lipid A analog, on endotoxin-induced cellular responses and acute lung injury. 888 83

The anti-inflammatory activity of pertussis toxin (Ptx) was compared to that of a noncatalytic mutant of pertussis toxin (9K/129G; Ptxm), which contains two amino acid substitutions in the A protomer, by using a rat model of inflammation. The toxins were administered intravenously 1 h prior to the injection of inflammatory stimuli. Ptx, but not Ptxm, inhibited neutrophil migration into peritoneal cavities in response to formyl-methionyl-leucyl-phenylalanine and lipopolysaccharide. The inhibitory effect of Ptx on neutrophil migration could not be explained by the ability of the toxin to induce leukopenia or neutropenia. The increase in skin vascular permeability induced by leukotriene B4, a powerful neutrophil chemotactic agent, was also inhibited only by Ptx. On the other hand, the increase in skin vascular permeability induced by histamine was potentiated by both toxins. These data show that Ptx inhibits neutrophil-mediated inflammation in vivo and that this effect is dependent on the ADP-ribosyltransferase activity of the A protomer.
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PMID:Role of pertussis toxin A subunit in neutrophil migration and vascular permeability. 903 26

Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator that causes hypotension, increases vascular permeability, and has been implicated in anaphylaxis, septic shock and several other inflammatory responses. PAF is hydrolyzed and inactivated by the enzyme PAF-acetylhydrolase. In the intact rat, a mesenteric vein infusion of lipopolysaccharide (LPS) served as an acute, liver-focused model of endotoxemia. Plasma PAF-acetylhydrolase activity increased 2-fold by 24 h following LPS administration. Ribonuclease protection experiments demonstrated very low levels of plasma-type PAF-acetylhydrolase mRNA transcripts in the livers of saline-infused rats; however, 24 h following LPS exposure, a 20-fold induction of PAF-acetylhydrolase mRNA was detected. In cells isolated from endotoxin-exposed rat livers, Northern blot analyses demonstrated that Kupffer cells but not hepatocytes or endothelial cells were responsible for the increased PAF-acetylhydrolase mRNA levels. In Kupffer cells, plasma-type PAF-acetylhydrolase mRNA was induced by 12 h, peaked at 24 h, and remained substantially elevated at 48 h. Induction of neutropenia prior to LPS administration had no effect on the increase in PAF-acetylhydrolase mRNA seen at 24 h. Although freshly isolated Kupffer cells contain barely detectable levels of plasma-type PAF-acetylhydrolase mRNA, when Kupffer cells were established in culture, PAF-acetylhydrolase expression became constitutively activated concomitant with cell adherence to the culture plates. Alterations in plasma-type PAF-acetylhydrolase expression may constitute an important mechanism for elevating plasma PAF-acetylhydrolase levels and an important component in minimizing PAF-mediated pathophysiology in livers exposed to endotoxemia.
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PMID:Cell-specific regulation of expression of plasma-type platelet-activating factor acetylhydrolase in the liver. 934 88

The effects of indomethacin, a cyclooxygenase inhibitor, upon plasma concentrations of prostaglandin E2 (PGE2), the febrile response, and metabolic and hematological alterations induced by lipopolysaccharide (LPS) were studied. Experimental endotoxemia was provoked via i.p. injection of 1.0 mg E coli LPS/kg in rats (group A). Indomethacin was introduced/os (2.5 mg/kg) 30 min prior to LPS challenge (group B). Pretreatment with this medication completely inhibited the hyperthermic response to LPS and eliminated the LPS-induced non-specific symptoms of anorexia, adipsia, reduced locomotory activity and gastrointestinal troubles. Plasma PGE2 concentrations increased as early as the 2nd h after the LPS challenge but were blocked when endotoxin application was preceded by indomethacin treatment. Indomethacin did not significantly influence hematological parameters. The dynamics of hematocrit and erythrocyte counts were similar in both groups with a decrease up to the 2nd h followed by an increase to maximum at post-treatment day 3. Pretreatment with indomethacin did not influence the endotoxin-induced leukopenia observed at the 2nd h or the accompanying neutropenia and left shift. Cyclooxygenase inhibition affected total protein concentrations; they were decreased in the early hours of the study (hours 4-6) in both groups. The later tendency towards increase in total protein concentrations was more expressed in animals from group B. Changes in blood glucose were characterized by a permanent tendency towards decrease after hour 2 of LPS challenge up to day 6 (group A). In group B, a similar tendency was observed, but glucose concentrations decreased between hours 2-6 and then returned to initial values.
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PMID:Effects of indomethacin on lipopolysaccharide-induced plasma PGE2 concentrations and clinical pathological disorders in experimental endotoxemia. 946 1

The objective of this study was to examine the role of copper in neutrophil development and function. Mice were made copper deficient by feeding dams a diet containing 1.05 microg copper starting at parturition. Control mice were fed the same diet containing 6 microg copper. The pups were weaned to the diet and killed when they were 5-6 wk old. Peripheral blood cell counts, margination and cell maturity were measured. The response to an intraperitoneal injection of lipopolysaccharide (LPS) was also determined. Copper deficiency resulted in twice as many neutrophils and fewer than half the number of lymphocytes. Half as many cells in copper-deficient mice expressed Ly-6G, a granulocytic marker of cell maturity. In addition, copper-deficient cells expressed only half the amount of Ly-6G per cell than was expressed by copper-adequate cells. This suggested that the cells were younger, or arrested in their maturation as a result of copper deficiency. An arrest of maturation has been proposed as the cause of neutropenia in human copper deficiency. Injection of LPS in copper-adequate mice resulted in twice as many Ly-6G-expressing cells in the periphery. LPS injection into copper-deficient mice resulted in a severe leukopenia but did not influence Ly-6G expression any more than did copper deficiency alone. LPS treatment caused an increase in myeloperoxidase activity associated with the lungs of copper-deficient mice. The results suggest that although the neutrophils of copper-deficient mice are immature, they can be sequestered by the lung when stimulated to do so.
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PMID:Arrested maturation of granulocytes in copper deficient mice. 980 34

A new C5a receptor antagonist, the cyclic peptide Phe-[Orn-Pro-D-cyclohexylalanine-Trp-Arg], (F-[OPdChaWR]), was tested for its ability to antagonize the neutropenic effects of both C5a and endotoxin in rats. Human recombinant C5a (2 microg kg(-1) i.v.) caused rapid neutropenia, characterized by an 83% decrease in circulating polymorphonuclear leukocytes (PMNs) at 5 min. Administration of F-[OPdChaWR] (0.3-3 mg kg(-1) i.v.), did not affect the levels of circulating PMNs but, when given 10 min prior to C5a, it inhibited the C5a-induced neutropenia by up to 70%. Administration of E. Coli lipopolysaccharide (LPS, 1 mg kg(-1) i.v.) also caused neutropenia with an 88% decrease in circulating PMNs after 30 min. When rats were pretreated with F-[OPdChaWR] (0.3 - 10 mg kg(-1) i.v.) 10 min prior to LPS, there was a dose-dependent antagonism of the neutropenia caused by LPS, with up to 69% reversal of neutropenia observed 30 min after LPS administration. These findings suggest that C5a receptor antagonists may have therapeutic potential in the many diseases known to involve either endotoxin or C5a.
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PMID:Effects of a new C5a receptor antagonist on C5a- and endotoxin-induced neutropenia in the rat. 1018 60

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