Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several episodes of neutropenia were observed in a child with glutathione synthetase deficiency (5-oxoprolinuria). Studies of the patient's glutathione-deficient neutrophils were undertaken to examine the responses of the cells to oxidative stress associated with phagocytosis. The patient's neutrophils contained 10--20% of normal glutathione content. Circulating neutrophils in infection-free periods appeared less mature than normal by morphologic criteria, suggesting increased cell turnover. The cells ingested particles, responded to chemotactic stimuli, and oxidized 1-14C glucose normally. However, following ingestion of particles, the cells accumulated excess hydrogen peroxide compared with normal cells, and showed impaired protein iodination and bacterial killing. Electron micrographs revealed damage to microtubules and membranous structures in the patient's neutrophils during phagocytosis. The level of glutathione in the cells appears inadequate to protect against peroxide generated during normal cell function, and the cells are thus damaged and rendered less effective in bacterial killing. The data provide evidence for a protective role of glutathione in normal neutrophil function.
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PMID:Oxidative damage to neutrophils in glutathione synthetase deficiency. 46 67

In 22 patients cuprophane capillary dialyzers reutilized in turn with four sets of liquids were used four times (Andante type in 13 and TAF-12 in 9 patients). The degree of biocompatibility and efficiency of elimination of small molecules was evaluated. During four-time reuse of dialyzers reutilized with sodium hypochlorite and with formaldehyde a reduction of intra-dialysis leukopenia, granulocytopenia and thrombocytopenia was not stated in blood of the patients. Activation of the complement system measured with the quantity of decrease of C3c fraction of the complement in the patients blood after 20 minutes of dialysis reduced essentially only at the fourth reuse of dialyzers (p < 0.01). Creatinine clearance measured always one hour after starting of the dialysis, did not change in succeeding reuse of dialyzers. Reutilization of dialyzers with hydrogen peroxide solution and formaldehyde caused essential reduction of ++intra-dialysis leukopenia and neutropenia (p < 0.001). There was lack of changes in ++intra-dialysis thrombocytopenia. Activation of the complement system was reduced essentially only after the fourth reuse of dialyzers (p < 0.001), but was also essentially lower (p < 0.05) than with dialyzers reutilized with sodium hypochlorite and with formaldehyde. Creatinine clearance practically did not change and at the fourth reuse of dialyzers it decreased on the average by 1.8%. Reutilization with acetic acid already at the second reuse of dialyzers essential (p < 0.001) and deepened decrease of intradialytic leukopenia and neutropenia and the activation of the complement system in course of succeeding reuses. Intradialytic thrombocytopenia was subjected to vestigal, not essential decrease. Creatinine clearance lowered a little but not essentially. At the fourth reuse of dialyzers it was lower on the average by 3.6% than the initial one. Reutilization with Dialina (stabilized blend of peracetic, acetic acid and hydrogen peroxide solution) caused essential (p < 0.001) and, in course of further reuses, deepening of lowering of intradialytic leukopenia and neutropenia as well as the activation of the complement system already at the second reuse. At the same time at the second and fourth reuse of dialyzers reutilized with Dialina the activation of the complement system was essentially lower than reutilized with the other liquids (p < 0.02). At the fourth reuse intradialytic thrombocytopenia also lowered essentially (p < 0.01). Creatinine clearance lowered a little more than with other liquids and at the second reuse of dialyzers was lower on the average by 5.6%, and at the fourth reuse--by 6.7% in relation to the new dialyzers.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Effect of re-utilization of cuprophan capillary dialysers with different liquids on their biocompatibility and effectiveness of elimination]. 146 37

Ethanol-induced gastric mucosal injury closely resembles an inflammatory response. Thus, in vivo and in vitro experimental models were used to assess whether ethanol is proinflammatory in concentrations likely to be encountered by the gastric mucosa during acute intoxication. Perfusing the rat gastric lumen with progressively increasing concentrations of ethanol (10%, 20%, and 30%) resulted in a dose-dependent increase in 51Cr-ethylenediaminetetraacetic acid clearance from blood-to-gastric lumen. Rendering the animals neutropenic (with antineutrophil serum) ameliorated the ethanol-induced mucosal injury; the degree of protection was directly related to the severity of neutropenia. Neither superoxide dismutase, catalase, nor sodium benzoate offered any protection against ethanol-induced injury, indicating that neither superoxide anion, hydrogen peroxide, nor the hydroxyl radical is involved. To assess further whether ethanol could exert proinflammatory effects an in vitro model consisting of cultured bovine microvascular endothelial cells and isolated human neutrophils was used. Ethanol at concentrations of 1.0%-4.0% (but not at 0.1%-0.5%) increased neutrophil adherence to endothelial cells and enhanced neutrophil-mediated endothelial cell injury. We conclude that ethanol is proinflammatory at concentrations that may be achieved in the gastric mucosa during acute intoxication. The ethanol-induced, neutrophil-mediated cell injury does not appear to involve oxy radicals.
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PMID:Ethanol-induced injury to the rat gastric mucosa. Role of neutrophils and xanthine oxidase-derived radicals. 231 75

Reactive oxygen species have been proposed as pathophysiological factors responsible for the hypodynamic circulatory response to gram-negative endotoxin. To test this hypothesis, we examined the cardiorespiratory effects of mechanistically different oxygen free radical scavenging agents during Escherichia coli endotoxemia in beagle dogs. Pentobarbital-anesthetized dogs were instrumented for repeated sampling of cardiorespiratory, hematologic, and tissue blood flow (radiolabeled 15-micron microspheres) indexes. Four groups were studied: 1) time-matched control dogs (n = 6); 2) dogs receiving only endotoxin (1.5 mg/kg; n = 6); 3) dogs receiving endotoxin and combination therapy with allopurinol (150 mg/kg) plus superoxide dismutase (5 mg/kg) and catalase (5 mg/kg; n = 6); and 4) dogs receiving endotoxin and deferoxamine (30 mg/kg; n = 5). Measured variables in control dogs were constant during the 4-h study, whereas endotoxin-injected dogs consistently demonstrated the following: 1) maintained reductions in blood pressure (greater than 45%), left ventricular systolic pressure (greater than 43%), left ventricular maximum rate of pressure development (+/- dP/dtmax) (greater than 41%), cardiac index (greater than 33%), and blood flow in all sampled tissues except liver and skeletal muscle; 2) transient tachypnea, bradycardia, and arterial acidosis; and 3) persistent neutropenia and hemoconcentration. Neither of the free radical scavenging protocols significantly improved measured variables during endotoxemia (P greater than 0.05). This lack of efficacy suggests that superoxide anion, hydrogen peroxide, and hydroxyl radical may lack primary pathophysiological importance during the development of E. coli endotoxicosis in intact dogs.
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PMID:Evidence for lack of importance of oxygen free radicals in Escherichia coli endotoxemia in dogs. 328 94

Cell suspensions enriched in human blood monocytes, obtained from normal peripheral blood by sedimentation on sodium diatrizoate-Ficoll gradients or from the blood of patients with neutropenia and monocytosis, accumulated malonyldialdehyde, a labile catabolite of lipid peroxidation, during incubations with polystyrene beads or heat-killed Staphylococcus epidermidis. Mixed blood leukocytes principally composed of granulocytes or granulocytes purified by density gradient sedimentation did not accumulate malonyldialdehyde during incubations with these particles, but did when ingesting particles containing linolenate. The phospholipid fatty acid composition of monocyte-enriched and purified granulocyte preparations from the same donors were compared. The molar fraction of arachidonate (20:4) in phospholipids from monocyte-rich preparations was 62% greater than that of purified granulocytes. The findings indicate that human monocytes, possibly because of a greater content of polyunsaturated fatty acids in their membranes, peroxidize a greater quantity of endogenous lipids than granulocytes during endocytosis. Normal human granulocytes have the capacity to peroxidize ingested lipids. However, mixed leukocytes from two patients with chronic granulomatous disease produced little malonyldialdehyde when engulfing linolenate-containing particles. Therefore the capacity to peroxidize lipid is related to cellular oxygen metabolism, a function in which chronic granulomatous disease granulocytes are dificient. Malonyldialdehyde chemically prepared by hydrolysis of tetramethoxypropane, by extraction from peroxidized linolenic acid, or purified from extracts of phagocytizing rabbit alveolar macrophages had bactericidal activity against Escherichia coli and S. epidermidis. Therefore, toxic catabolites of lipid hydroperoxides may potentiate the bactericidal activity of hydrogen peroxide in mononuclear phagocytes.
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PMID:Lipid peroxidation by human blood phagocytes. 485 10

Single cytokine therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) has been shown to be effective in decreasing the respective periods of neutropenia and thrombocytopenia following radiation- or drug-induced marrow aplasia. The combined administration of IL-3 and GM-CSF in normal primates suggested that a sequential protocol of IL-3 followed by GM-CSF would be more effective than that of GM-CSF alone in producing neutrophils (PMN). We investigated the therapeutic efficacy of two combination protocols, the sequential and coadministration of recombinant human IL-3 and GM-CSF relative to respective single cytokine therapy, and delayed GM-CSF administration in sublethally irradiated rhesus monkeys. Monkeys irradiated with 450 cGy (mixed fission neutron:gamma radiation) received either IL-3, GM-CSF, human serum albumin (HSA), or IL-3 coadministered with GM-CSF for days 1 through 21 consecutively postexposure, or IL-3 or HSA for days 1 through 7 followed by GM-CSF for days 7 through 21. All cytokines and HSA were injected subcutaneously at a total dose of 25 micrograms/kg/d, divided twice daily. Complete blood counts (CBC) and platelet (PLT) counts were monitored over 60 days postirradiation. The respiratory burst activity of the PMN was assessed flow cytometrically, by measuring hydrogen peroxide (H2O2) production. Coadministration of IL-3 and GM-CSF reduced the average 16-day period of neutropenia and antibiotic support in the control animals to 6 days (P = .006). Similarly, the average 10-day period of severe thrombocytopenia, which necessitated PLT transfusion in the control animals, was reduced to 3 days when IL-3 and GM-CSF were coadministered (P = .004). The sequential administration of IL-3 followed by GM-CSF had no greater effect on PMN production than GM-CSF alone and was less effective than IL-3 alone in reducing thrombocytopenia. PMN function was enhanced in all cytokine-treated animals.
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PMID:Combination protocols of cytokine therapy with interleukin-3 and granulocyte-macrophage colony-stimulating factor in a primate model of radiation-induced marrow aplasia. 821 92

Hematopoietic stem cells, CD34 positive cells, were isolated from the peripheral blood of three patients with malignant lymphoma, and were cultivated in suspension for 14 days in the presence of cytokines, including granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interleukin-3 and stem cell factor. The stimulation of cell proliferation and differentiation into mature neutrophils was most effective when all these cytokines were used in combination. Mature neutrophils differentiated in vitro gained the ability to ingest latex spheres and to produce hydrogen peroxide in response to phorbol myristate acetate. These findings raise the possibility that the prolonged neutropenia following high dose chemotherapy could be ameliorated by the transfusion of autologous neutrophils expanded and differentiated in vitro.
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PMID:In vitro expansion of mature neutrophils from isolated peripheral blood stem cells. 934 94

Ex vivo expanded CD34+ progenitor cells from fresh or cryopreserved primate bone marrow, induced to granulocytic differentiation with growth factors, were investigated to determine whether myeloid cells produced in liquid cultures have the normal biologic functions needed for the treatment of patients with neutropenia following high-dose chemotherapy or therapeutic or accidental radiation exposure. Human and simian (baboons or macaques) CD34+ cells were cultured with granulocyte-colony stimulating factor (G-CSF), stem cell factor (SCF), interleukin-1 (IL-1), IL-3, and IL-6, and assessed at 14 days of culture for their capacity to respond to different functional tests. Immunostaining revealed that human ex vivo expanded cells contained myeloperoxydase (MPO, 82% +/- 8%) and lactoferrin (LF, 30% +/- 6%) in their granules. Maturation of cultured cells was associated with stimulated chemotactic responsiveness and respiratory burst activity (superoxide anion and hydrogen peroxide production) in expansions from human, baboon, and macaque CD34+ progenitor cells. Mature cells obtained from ex vivo expansion of selected cryopreserved human bone marrow CD34+ cells presented reduced but significant functional activities (chemotactic responsiveness and hydrogen peroxide production) when compared with human peripheral blood neutrophils. The validation of nonhuman primate ex vivo expansion systems may permit their use as models of irradiation. The feasibility of ex vivo expansion from cryopreserved bone marrow cell samples may offer considerable opportunity for banking bone marrow for autologous transfusion.
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PMID:Functional studies of maturing myeloid cells during ex vivo expansion for treatment of aplasia: feasibility of ex vivo expansion from cryopreserved bone marrow cell samples. 950 83

Neutropenia and impairment of neutrophil function are commonly observed in patients with human immunodeficiency virus (HIV) infections. The HIV regulatory protein Tat is known to exert immunosuppressive effects. Alcohol is known also to be an immunosuppressive factor, and as alcohol abuse is common among HIV infected hosts, both factors may interact in an additive or synergistic fashion to further impair the host defenses of these patients. In order to test this possibility, endotoxin-induced neutrophil beta2-integrins CD11b and CD18 expression, phagocytosis, and hydrogen peroxide generation were examined in normal and HIV-1 Tat-transgenic mice in the absence and presence of ethanol intoxication. Acute ethanol intoxication was induced in mice (body weight of 25+/-1 g) by an intraperitoneal (ip) injection of ethanol (3 g/kg, 20% in normal saline). Thirty min later, the animals were given an ip injection of endotoxin (20 microg in 0.2 ml of saline/mouse). Vehicle-treated controls received an ip injection of saline without ethanol or endotoxin. Two hr after endotoxin administration, the animals were killed to determine neutrophil functions with flow cytometry. The baseline expression of CD11b and CD18 was similar in normal nontransgenic and Tat-transgenic mice. Endotoxin administration significantly up-regulated CD11b and CD18 expression in normal mice. This up-regulation was suppressed in Tat-transgenic mice. Ethanol intoxication inhibited endotoxin-induced CD11b and CD18 expression in normal mice and totally abolished endotoxin-induced CD11b and CD18 expression in Tat-transgenic mice. Neutrophil phagocytic activity in normal and Tat-transgenic mice was similar. Ethanol intoxication produced a similar inhibition of phagocytosis in both study groups. Endotoxin suppressed phagocytosis in normal mice, and this suppression was more pronounced in Tat-transgenic mice. Spontaneous and phorbol myristate acetate (PMA)-stimulated hydrogen peroxide generation by circulating neutrophils (PMNs) were similar in normal and Tat-transgenic mice. Neither ethanol nor endotoxin affected hydrogen peroxide generation by PMNs. These data show that both Tat and alcohol significantly impair PMN function, and this may be a mechanism leading to the increased susceptibility of the HIV-infected host to bacterial infection.
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PMID:The human immunodeficiency virus type I Tat protein potentiates ethanol-induced neutrophil functional impairment in transgenic mice. 988 49

Reactive oxygen metabolites (ROMs) contribute to the pathophysiology of intestinal inflammation. Our aim was to ascertain the involvement of ROMs in experimental ileitis in rats produced by toxin A of Clostridium difficile. Intraluminal toxin A caused a significant increase in hydroxyl radical and hydrogen peroxide production by ileal microsomes starting 1 h following toxin exposure and peaking at 2-3 h, and this was inhibited by pretreatment with DMSO, a ROM scavenger, or superoxide dismutase (SOD), which inactivates ROMs. In contrast, mucosal xanthine oxidase increased only slightly after toxin A exposure, and allopurinol, an inhibitor of xanthine oxidase, had no effect on toxin A-associated intestinal responses. Induction of neutropenia resulted in reduction of toxin-mediated free radical formation, fluid secretion, and permeability. The enterotoxic effects of C. difficile toxin A were associated with increased ROM release in ileal tissues, and the ROM inhibitors DMSO and SOD inhibited these effects. This suggests that ROMs released during toxin A enteritis are released primarily from neutrophils invading the inflamed bowel segment.
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PMID:Participation of reactive oxygen metabolites in Clostridium difficile toxin A-induced enteritis in rats. 995 Aug 23


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