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)

Two children with glycogen storage disease type Ib associated with numerous recurrent bacterial infections as a result of neutropenia and neutrophil dysfunction were treated with recombinant human granulocyte colony-stimulating factor (G-CSF). One of the two patients was previously treated with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF); therapy had to be discontinued because of severe local side effects. Both colony-stimulating factors at dosages of 3 and 8 micrograms/kg/per day, respectively, increased the average neutrophil counts from less than 300 cells/microliters to more than 1200 cells/microliters. Two subpopulations of neutrophils could be identified by their capacity to produce H2O2: one subpopulation generated H2O2 normally and a second was defective in H2O2 production. The doses of G-CSF effectively enhanced and maintained that subpopulation of neutrophils which produced normal amounts of H2O2. Moreover, these colony-stimulating factor-induced neutrophils demonstrated effective phagocytosis of zymosan particles and killing of staphylococci. Chemotaxis was decreased and could not be normalized by treatment with G-CSF. We conclude that maintenance treatment with G-CSF improved the quality of life in both patients: The number and severity of bacterial infections decreased markedly during treatment. Long-term treatment with G-CSF (12 and 10 months, respectively) was well tolerated, and no adverse clinical events were observed.
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PMID:Granulocyte and granulocyte-macrophage colony-stimulating factors for treatment of neutropenia in glycogen storage disease type Ib. 171 75

To stimulate granulopoiesis, we gave recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF; 120 microgram/m2/d) to a patient with congenital neutropenia. The treatment resulted in marked increases in white blood cell counts (maximum, 17,400/microL), consisting mainly of eosinophils (maximum, 13,050/microL) and monocytes (maximum, 1305/microL), rather than neutrophils (maximum, 798/microL). Circulating phagocytes (97% eosinophils) derived after GM-CSF treatment were less effective in chemotaxis, slower but equally effective in phagocytosis, and more effective in H2O2 production compared with normal control neutrophils, but comparable in chemotaxis and H2O2 production to control eosinophils. Before GM-CSF treatment, the bone marrow showed a maturation defect in the neutrophilic series that persisted after treatment despite marked increases in mature cells of other lineages. In vitro agar culture of bone marrow cells before GM-CSF treatment showed a normal number of granulocyte colonies; however, maturation was limited to the metamyelocyte stage. Although the absolute number and cycling rates of myeloid colony forming cells (predominantly eosinophils) increased after treatment, the maturation defect in the neutrophilic series persisted. The finding that GM-CSF induced stimulation of proliferation, which was coupled with maturation in the eosinophilic and monocytic but not the neutrophilic components, suggests that this patient had an intrinsic cellular or humoral defect in neutrophil maturation.
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PMID:Stimulation of myelopoiesis in a patient with congenital neutropenia: biology and nature of response to recombinant human granulocyte-macrophage colony-stimulating factor. 240 22

The mechanisms underlying drug-induced neutropenia are poorly characterized. We have examined the mechanism of suppression of granulocytopoiesis by captopril and penicillamine using human and canine bone marrow cells in an in vitro culture system. Addition of captopril caused no significant change in granulocyte-macrophage colony formation at concentrations up to 30 micrograms/ml. In the presence of CuSO4 (1-3 micrograms/ml), however, captopril caused significant inhibition of colony growth (p less than 0.05). Penicillamine, another agent associated with neutropenia and, like captopril, having a reactive thiol group, also inhibited colony formation in the presence of copper. Chemical congeners of captopril lacking a reactive thiol group and enalaprilic acid, an alternative angiotensin-converting enzyme (ACE) inhibitor, failed to show inhibition, suggesting that the thiol group and not ACE inhibition was responsible. Analysis of day-7 colonies (98% neutrophilic) and day-21 colonies (37% neutrophilic, 30% macrophagic, 27% eosinophilic, and 6% mixed) showed that neutrophil-containing colonies, but not nonneutrophilic colonies were inhibited by the addition of captopril plus copper. Catalase totally reversed the inhibition of colony formation caused by these agents. Direct measurement of oxygen consumption in the presence of captopril showed marked enhancement with the addition of CuSO4 and a 48% reduction in the presence of added catalase. These data indicate that drugs with a reactive thiol group can interact with copper to generate H2O2, which can be toxic to neutrophilic progenitor cells. We postulate that this may be an important mechanism for drug-associated neutropenia and a general mechanism for drug-induced marrow cell injury.
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PMID:Suppression of in vitro granulocytopoiesis by captopril and penicillamine. 284 Nov 47

Drugs possessing membrane stabilizing activity might act to diminish the augmented microvascular permeability resulting from acute lung injury. To test this rats were pretreated with quinidine, procainamide, or lidocaine and then given the lung injury-inducing agent thiourea. Vascular permeability, assessed as the extravascular accumulation of radiolabeled protein, was increased more than threefold by thiourea. This increase was diminished by 29, 34, and 43% after pretreatment with procainamide, quinidine, and lidocaine, respectively. Lidocaine also returned the thiourea-induced increase in lung wet weight-to-dry weight ratios to control levels. This protection was not likely due to hemodynamic effects of these agents, since no differences were noted in cardiac output between pretreated rats and those receiving thiourea alone and a small increase in mean pulmonary arterial pressure in the lidocaine-pretreatment group was the only difference noted. O2 metabolites have been implicated in the pathogenesis of thiourea-induced lung injury. None of these agents scavenged O2- or H2O2 directly, but quinidine and procainamide diminished in vitro neutrophil O2- and H2O2 production, and lidocaine inhibited neutrophil H2O2 production. However, neutropenia (PMN less than 100/ml) induced with either vinblastine or cyclophosphamide (Cytoxan) failed to prevent thiourea-induced increases in pulmonary vascular protein leak. In conclusion, procainamide, quinidine, and lidocaine diminished lung injury in rats after thiourea. Although these agents diminish PMN O2 metabolite production in vitro their salutary role in thiourea-induced lung injury appears to be through an unknown mechanism that is independent of their effects on neutrophil O2 metabolite-dependent toxicity.
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PMID:Antiarrhythmic agents diminish thiourea-induced pulmonary vascular protein leak in rats. 312 76

Neutrophils have been implicated in the pathogenesis of acute lung injury associated with clinical and experimental sepsis. Data from in vitro systems and experimental animals have suggested that neutrophil-derived oxidants, particularly H2O2, may be primarily responsible for endothelial damage, vasoconstriction, and lung edema. With the use of endotoxin infusion as an in vivo model of sepsis we tested the hypothesis that pretreatment with catalase, a peroxide scavenger, would ameliorate the resultant changes in pulmonary vasoconstriction and lung fluid balance. Paired experiments were performed in 16 goats with chronic lung lymph fistulas. One group of animals (n = 7) received endotoxin first alone and then again, several days later, after pretreatment with Ficoll-linked catalase. As a control, identical experiments were performed in a separate group (n = 6) with Ficoll-linked albumin substituted for Ficoll-catalase. A third group (n = 3) was given endotoxin alone and then again during a continuous infusion of catalase. Plasma and lymph levels of catalase were comparable to or exceeded those previously shown to be completely protective in isolated perfused lung preparations and in vitro systems. Endotoxin caused neutropenia, pulmonary arterial hypertension, decreased cardiac output, and increases in lymph flow to approximately three times base line, with a return of all variables toward control values by 6 h. Catalase pretreatment produced no significant differences in any of these variables. These experiments do not support a role for H2O2 as a mediator of acute lung injury due to endotoxemia.
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PMID:Effect of intravenous catalase on the pulmonary vascular response to endotoxemia in goats. 328 99

During chemotherapy for acute leukemias, severe neutropenia allows acquisition of life-threatening infections that are difficult to clear with antibiotics alone. With return of myelopoiesis, even severe infections often improve dramatically. We have sequentially examined oxidative metabolic responses of polymorphonuclear leukocytes (PMNL) from 30 patients with acute leukemias before induction chemotherapy and after recovery of myelopoiesis (circulating PMNL greater than 500/microL). Maximal oxidative metabolic responses were quantitated by flow cytometric analysis of H2O2-dependent oxidation of intracellular 2',7'-dichlorofluorescin (DCFH) in individual PMNL after stimulation with phorbol myristate acetate (PMA). Resting PMNL oxidized a mean of 6.8 attomoles (amol) DCFH/cell/15 min, with no difference between normal or patients' PMNL. PMA-stimulated normal PMNL oxidized 183 +/- 35 amol/cell (mean +/- SD, n = 120). In patients' PMNL obtained before chemotherapy, the mean DCFH oxidation was not significantly different from controls (216 +/- 78 amol/cell). However, 11 of 22 samples revealed populations of granulocytes with increased (primed) oxidative responses; seven of these 11 patients had proven or suspected infection at presentation. At recovery from chemotherapy-induced neutropenia, PMNL from 19 of 21 patients possessed one or more significant subpopulations with primed oxidation in response to PMA. In these 19 patients, 61% +/- 8% of PMNL comprised primed populations that oxidized 503 +/- 46 amol/cell. Oxidative activity was most pronounced in patients with proven or clinically suspected infections (with 41% +/- 9% of PMNL oxidizing 615 +/- 79 amol/cell). However, oxidative responses to PMA were also significantly increased in recovery PMNL from ten patients without clinical or laboratory evidence of active infection (79% +/- 11% of PMNL primed to oxidize 402 +/- 29 amol/cell). The peak responses of the primed subpopulations were short-lived and generally lasted three days or less, although oxidative responses remained elevated above normal for a week or more. All of the patients with increased PMNL responsiveness survived their hospitalization. In contrast, PMNL from four patients had a significant population (18% to 82% of cells) with reduced responsiveness. Two of these four patients (with 71% and 75% subnormal cells) died during this induction attempt; the third died during a second induction attempt; only one survived to discharge. The clinical significance of these phenomena is yet to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Altered oxidative product formation in neutrophils of patients recovering from therapy for acute leukemia. 370 56

Human granulocytes harvested from uremic volunteers 15 min after the initiation of dialysis (at the nadir of neutropenia) were compared to predialysis controls. These intradialysis cells had a significant defect in peak luminol-enhanced chemiluminescence in response to opsonized zymosan, f-Met-Leu-Phe, and phorbol myristate acetate relative to predialysis control cells from the same patients. This defect could not be explained by a decrease in PMN myeloperoxidase concentration. H2O2 secretion by intradialysis cells (2 patients) was also depressed relative to predialysis controls. The ability to perform an independent function, orientation (polarization), was normal in both pre- and intradialysis cells relative to control. Whereas 125I-labeled formyl peptide binding studies demonstrated identical values for affinity and receptor number for predialysis and normal control cells, intradialysis cells displayed a 27% decrease in receptor number. This decrease in available receptor number. This decrease in available receptors may be related to the decreased chemiluminescence observed in response to f-Met-Leu-Phe. Furthermore, the results are consistent with the hypothesis that a defective PMN population remains in the circulation during the neutropenia of hemodialysis.
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PMID:A defect in the oxidative metabolism of human polymorphonuclear leukocytes that remain in circulation early in hemodialysis. 629 74

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

Hemodialysis with cellulose membranes causes a complement-mediated neutropenia. Changes in neutrophil function have also been reported; however, it is unclear if these changes indicate a direct effect of the membrane on neutrophils or if they are a consequence of the neutropenia. We tested the hypothesis that neutrophil oxidative burst activity is enhanced during dialysis with cellulose membranes. Resting and Staphylococcus aureus-stimulated H2O2 production were determined predialysis and in blood entering and leaving the dialyzer during the first 30 min of dialysis and in blood leaving the membrane module in a single-pass on-line model of hemodialysis. Resting H2O2 production increased slightly but significantly during the first 30 min of dialysis. Transit of neutrophils through the dialyzer caused a marked increase in stimulated H2O2 production, indicating priming of the oxidative burst. However, priming was limited to the first 5 min of dialysis before the onset of neutropenia. In contrast, stimulation and priming of H2O2 production persisted throughout 30 min of single-pass on-line perfusion. These results indicate that cellulose membranes both stimulate and prime neutrophil oxidative burst activity but that these effects are partially obscured by neutropenia.
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PMID:Hemodialysis with cellulose membranes primes the neutrophil oxidative burst. 857 99

Studies were conducted with rats to investigate whether exposure to carbon monoxide (CO) at concentrations frequently found in the environment caused lung injury mediated by nitric oxide (*NO)-derived oxidants. Lung capillary leakage was significantly increased 18 h after rats had been exposed to CO at concentrations of 50 ppm or more for 1 h. An elevation of *NO during CO exposure was demonstrated by electron paramagnetic resonance spectroscopy. There was a 2.6-fold increase of *NO over control in the lungs of rats exposed to 100 ppm CO. A qualitative increase in the concentration of H2O2 was also detected in lungs during CO exposure, and this change was caused by *NO as it was inhibited in rats pretreated with the nitric oxide synthase inhibitor, Nomega nitro-l-arginine methyl ester (l-NAME). Production of *NO-derived oxidants during CO exposure was indicated by an elevated concentration of nitrotyrosine in lung homogenates. The CO-associated elevations in lung capillary leakage and nitrotyrosine concentration did not occur when rats were pretreated with l-NAME. CO exposure did not change the concentrations of endothelial or inducible nitric oxide synthase in lung and leukocyte sequestration was not detected as a consequence of CO exposure. CO-mediated lung leak and nitrotyrosine elevation were not affected by neutropenia. We conclude that CO exposure elevates the steady-state concentration of *NO in lungs. Consequences from this change include increases in the concentration of reactive oxygen species, production of *NO-derived oxidants such as peroxynitrite, and physiological evidence of lung injury.
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PMID:Pulmonary vascular stress from carbon monoxide. 988 87


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