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)

We describe a case of quinidine-induced agranulocytosis in which in vitro marrow culture studies suggested immune inhibition of committed human granulocyte-macrophage progenitors (CFU-GM). Autologous, but not allogeneic, inhibition of CFU-GM was seen with 'acute' serum from the patient in the presence of quinidine but not other drugs. Cytotoxic antibodies to mature granulocytes were not found. These studies provide a novel mechanism for drug-induced neutropenia and suggest that a battery of in vitro assays of progenitor and of mature granulocyte cytotoxicity might identify offending agents in suspected drug-induced neutropenias.
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PMID:Quinidine-induced neutropenia: report of a case with drug-dependent inhibition of granulocyte colony generation. 644 17

The mechanism of inhibition of neutrophilic granulopoiesis by ethanol has not been well characterized. Possible mechanisms investigated include: (a) a direct toxic effect on the granulocyte-macrophage cluster-colony forming unit (CFU-GM), and/or (b) inhibition of production of CFU-GM proliferation stimulating factor activity (CSA) from T lymphocytes (T cells). Addition of as much as 600 mg% ethanol to T-cell- and monocyte-depleted light-density marrow (TMoDLDBM) cells from humans in soft agar cultures which were stimulated with an exogenous source of CSA did not inhibit the CFU-GM proliferation, suggesting that ethanol has no direct toxic effect on the CFU-GM. T cells obtained from the blood of normal humans were cultured in the presence of phytohemagglutinin with 100 to 600 mg% ethanol. Cell-free conditioned media (CM) from these cultures were tested for CSA concentration by their capacity to stimulate proliferation of CFU-GM from human TMoDLDBM or rat whole bone marrow cells. The results indicated that ethanol at a concentration greater than 100 mg% inhibited CSA production from T cells. There was no evidence for production of an inhibitor of CFU-GM proliferation from T cells in the presence of ethanol. These results suggest that the neutropenia which occurs in relation to alcohol abuse may in part be related to decreased CSA production from T cells.
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PMID:Mechanism of inhibition of granulopoiesis by ethanol. 660 76

Lithium (Li) is a known stimulator of steady-state granulopoiesis, influencing both pluripotential (CFUS) and granulocyte-macrophage committed stem cell (CFUGM) populations. Li has therefore been suggested to be an effective agent to reduce the neutropenia that often is seen after either cytotoxic chemotherapy or radiotherapy protocols. In this report, we have examined bone marrow and spleen cells for their recovery patterns of CFUS, CFUGM, CFUE, BFUE and 59Fe-incorporation, along with the usual peripheral blood indices (packed red cell volume, WBC and differential) from mice administered Li after receiving 200 rad whole body irradiation. Li increased granulopoietic recovery as measured by significant elevations in both marrow and spleen derived CFUGM compared to those values obtained from radiation controls. Significant elevation in the WBC, consisting mainly of neutrophils, was also observed. Bone marrow and splenic derived erythroid stem cells (CFUE, BFUE) and % 59Fe-incorporation measured from peripheral blood, femur and spleen were all slightly reduced, but not to a significant degree to alter the packed red cell volume. The CFUS populations from both irradiated groups (control and Li-treated) were depressed when compared to normal non-irr controls and this degree of suppression was greater in the Li-treated group. These results document the ability of Li to stimulate the recovery of granulopoiesis after radiation-induced hematopoietic injury and suggest Li may be useful in ameliorating the neutropenia that can often develop after routine radiotherapy protocols.
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PMID:Lithium stimulates the recovery of granulopoiesis following acute radiation injury. 661 90

Blood granulocyte-macrophage progenitors (CFU-GM) were studied in 116 normal, 32 neutropenic and 22 neutrophilic subjects through a double layer agar culture system. The neutropenic group showed significantly lower than normal mean value of CFU-GM per ml of blood, the blood concentration of CFU-GM being within normal limits in 25/32 subjects (78.1%). The neutrophilic group showed significantly higher than normal mean value of blood CFU-GM, and a normal blood concentration of CFU-GM was found in 17/22 patients (77.3%). Within the neutropenic group the concentration of blood CFU-GM was lower than normal in 5/11 (45.4%) patients with less than 1.1 x 10(9) polymorphonuclear leukocytes (PMN) and only in 2/21 (9.5%) patients with more than 1.1 x 10(9)/1 PMN. Within the neutrophilic group the concentration of blood CFU-GM was normal in all 12 subjects having less than 10.5 x 10(9)/1 PMN, while 5/10 (50%) patients with more than 10.5 x 10(9)/1 PMN had higher than normal blood concentration of CFU-GM. The mean leukocyte CSA of the normal, neutropenic and neutrophilic groups did not differ significantly. Within the neutropenic group the CSA was lower than normal in 3/11 (27%) patients with less than 1.1 x 10(9)/1 PMN and in 2/20 (10%) patients with more than 1.1 x 10(9)/1 PMN. Within the neutrophilic group the CSA was normal in all patients with less than 10.5 x 10(9)/1 PMN and it was higher than normal in 2/10 (20%) patients with more than 10.5 x 10(9)/1 PMN. A pathophysiological approach to both neutropenia and neutrophilia, according to PMN and CFU-GM blood concentration, is discussed.
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PMID:Correlation between blood granulocyte progenitor cells and polymorphonuclear leukocytes. A tentative pathophysiological subgrouping of neutropenic and neutrophilic patients. 667 Nov 34

A 19-year old girl with severe cyclical neutropenia associated with life-threatening infection and who responded dramatically to the administration of oral prednisolone is described. During reduction and eventual cessation of steroid therapy normal or near normal neutrophil counts have been maintained, and there has been parallel improvement in clinical well-being. Prior to therapy and at a time of peak blood neutrophil count low numbers of granulocyte-macrophage progenitor cells (CFU-C) were found in the patient's bone marrow, and her lymphocytes co-cultured with normal marrow failed to show the inhibitory effect normally seen with normal lymphocytes. The findings in this patient are compared with those in the two other cases where cyclical neutropenia has been shown to respond to steroids.
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PMID:Steroid responsive cyclical neutropenia. 669 4

The cycling of blood cell counts in grey collie dogs with cyclic hematopoiesis can be eliminated by treatment with oral lithium carbonate. To explore the mechanism by which lithium alters this stem cell disorder, studies of bone marrow granulocyte-macrophage progenitor cells (CFU-C), neutrophil colony-forming cells (neutrophilic CFU-C), and colony-stimulating activity (CSA) were performed. In untreated dogs, the proportions of CFU-C were found to fluctuate cyclically, but the cyclic fluctuations in neutrophil colony-forming cells were even more marked, with numbers decreasing to undetectable levels during each period of neutrophilia. Dogs on lithium, however, did not cycle the numbers of total or neutrophilic CFU-C. Tritiated thymidine suicide rates were not altered by treatment with lithium. Serum CSA levels and bone marrow cell elaboration of CSA were not increased by lithium. These studies suggest that lithium corrects cyclic neutropenia by a direct effect on the differentiation and proliferation of CFU-C; normalization of the proportion of CFU-C that enter neutrophilopoiesis appears to be an important effect of the lithium therapy.
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PMID:Cyclic hematopoiesis: effects of lithium on colony-forming cells and colony-stimulating activity in grey collie dogs. 697 96

Colony-forming capacities were studied in three Japanese children with Shwachman's syndrome (chronic neutropenia and exocrine pancreatic insufficiency). Bone marrow granulocyte-macrophage colony-forming cells assayed in a soft agar culture were markedly reduced in all three cases. The cytochemical examination of granulocyte-macrophage colonies by a new technique revealed that 90% of the colonies by a new technique revealed that 90% of the colonies consisted exclusively of granulocytes. Erythroid colony-forming cells assayed in a plasma clot culture were significantly reduced in two of the three cases. Bone marrow phagocytic cells did not suppress granulopoiesis in contrast to the cases of idiopathic aplastic anemia. Moreover, the patient serum did not inhibit granulopoiesis of normal bone marrow cells. These results have been discussed with the possibility of involving the hemopoietic stem cells and other additional factors.
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PMID:Hemopoietic colony-forming cells in Shwachman's syndrome. 711 96

We studied the effect of the H2-receptor antagonists, cimetidine and metiamide, on in vitro myeloid colony formation by bone marrow cells from seven normal volunteers and two patients with a cimetidine-associated neutropenia. A cimetidine concentration of 500 microgram/ml produced 50% inhibition of normal granulocyte-macrophage colony formation, and 1000 microgram/ml of cimetidine completely suppressed proliferation. The inhibitory effect of metiamide occurred at lower concentrations: 50% inhibition at 250 microgram/ml and 95% inhibition at 350 microgram/ml. Cimetidine had a similar inhibitory effect on colony formation by recovery marrow from the two patients with cimetidine-associated neutropenia. Treatment of autologous and allogeneic marrows with patients' acute phase sera and cimetidine failed to show evidence of antibody-mediated suppression of granulopoiesis. Our results indicate that at sufficiently high concentrations, cimetidine and metiamide inhibit human bone marrow myeloid colony formation in vitro. These findings are consistent with the hypothesis that H2-receptor antagonists may produce neutropenia in a dose-related fashion by injury to granulocytic progenitor cells in vivo.
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PMID:Cimetidine and granulopoiesis: bone marrow culture studies in normal man and patients with cimetidine-associated neutropenia. 744 23

During the administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) or granulocyte-macrophage CSF (rhGM-CSF) we studied the early and late changes of membrane antigen density on neutrophils. RhG-CSF and rhGM-CSF both caused an early transient reduction in blood neutrophilic granulocyte-concentration within the first 30 min after treatment followed by a marked later increase during the subsequent 24 h. During the early neutropenia quantitative flow cytometry showed an associated marked increase in the density of membrane CD11b from 169 x 10(3) before to 568 x 10(3) A.U. per cell induced by rhGM-CSF but a non-significant change by rhG-CSF, suggesting that different mechanisms may be responsible for the transient neutropenia. The subsequent neutrophil granulocytosis was followed by a significantly (P < 0.05) increased density of the CD14 antigen from 6.1 x 10(3) before to 15.9 x 10(3) A.U. per cell during treatment with rhG-CSF, but not by rhGM-CSF administration. These results demonstrate that the two cytokines may affect the function of neutrophilic granulocytes in different ways. The increased expression of CD11b could explain some of the side-effects during treatment with rhGM-CSF. The upregulation of CD14 induced by rhG-CSF may be clinically relevant, as CD14 is an opsonic receptor for lipopolysaccharide binding proteins, acting in the defence against Gram-negative bacterial infections.
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PMID:Different membrane expression of CD11b and CD14 on blood neutrophils following in vivo administration of myeloid growth factors. 750 10

Congenital neutropenia (Kostmann's syndrome [KS]) is an autosomal recessive syndrome that is characterized by profound neutropenia, resulting in major clinical infections and death. Since the neutropenia and symptoms in KS improve in response to exogenous administration of granulocyte colony-stimulating factor (G-CSF), we studied bone marrow cytokine (G-CSF, granulocyte-macrophage CSF [GM-CSF], and interleukin-6) production under both basal and stimulated conditions. No differences in G-CSF, GM-CSF, or IL-6 gene expression were found in bone marrow stromal cells between normal controls and KS patients, and all three cytokines were detected by enzyme-linked immunosorbent assay (ELISA) in medium conditioned by bone marrow stromal cells from normal donors and patients with KS. Each KS patient tested had detectable, functional G-CSF in their own serum before exogenous G-CSF administration. Since G-CSF production appeared normal in KS patients, we then asked whether we could detect structural defects in the signaling portion of G-CSF receptor genes. Polymerase chain reaction (PCR) amplification of the G-CSF receptor transmembrane region alone, and of the transmembrane plus cytosolic portions of the receptor, yielded the size products predicted from the sequences of the normal G-CSF receptor. Single-strand conformational polymorphism (SSCP) analysis of G-CSF receptor PCR products demonstrated no variance in structural conformation between KS patients and normal subjects. These results demonstrate that bone marrow stromal cells in patients with KS secrete normal concentrations of functional G-CSF and suggest that the neutropenia in KS patients is caused by an inability of neutrophilic progenitor and precursor cells to respond to normal, physiologic levels of G-CSF. Such a defect, clinically responsive to pharmacologic doses of G-CSF, might be caused by defects in the post-G-CSF receptor signal transduction pathway.
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PMID:Granulocyte colony-stimulating factor (G-CSF) production and G-CSF receptor structure in patients with congenital neutropenia. 751 Jan 42


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