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)

The administration of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) causes a transient leucopenia. Radionuclide labelling studies showed this to be due to margination of neutrophils and monocytes predominantly in the pulmonary vasculature. No evidence of complement activation was found. A rapid in-vivo rise in neutrophil cellular adhesion molecule (CAM) expression was observed paralleling the development of the neutropenia. Neutrophils exposed to rhGM-CSF in-vitro showed similar rapid increases in CAM expression. The adherence of chromium-labelled neutrophils to endothelial cell cultures was modestly but highly significantly increased by rhGM-CSF, an effect that was reduced by the binding of a monoclonal antibody to the beta chain of neutrophil CAM. The margination of phagocytic cells induced by rhGM-CSF administration is therefore likely to be due at least in part to increased expression of adhesion promoting glycoproteins. The demargination, however, occurred at a time when neutrophil CAM expression was still high, suggesting that dissociation of the neutrophil-endothelial cell interaction depends on factors other than downregulation of CAM expression. In-vivo modulation of phagocyte CAMS and adhesive properties by GM-CSF may be of importance in the normal inflammatory response.
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PMID:Granulocyte macrophage colony stimulating factor induced changes in cellular adhesion molecule expression and adhesion to endothelium: in-vitro and in-vivo studies in man. 264 37

Clonal expansions of CD3+ large granular lymphocytes (LGL) have been classified as T-LGL leukemia. The majority of patients with T-LGL leukemia have a chronic disease (years) manifested often by severe neutropenia, rheumatoid arthritis, and mild-to-moderate splenomegaly. The characteristic phenotype of the leukemic LGL is CD3+, CD8+, CD16+, CD57+, and CD56-. In this report we describe an aggressive variant of T-LGL leukemia in which leukemic LGL also expressed CD56, as identified by two-color flow-cytometry analysis. In contrast to the chronic nature typical of T-LGL leukemia, these patients presented with a severe systemic illness that was rapidly progressive and resistant to treatment. Atypical clinical features included rapidly increasing spleen size to massive proportions, extensive lymphadenopathy, and the presence of B symptoms (fever, nightsweats, weight loss). Hematologic and pathologic features were also unusual for T-LGL leukemia. These patients had very high LGL counts at diagnosis (range 11,692 to 26,312 microL), which increased rapidly despite treatment. Histopathologic examination of splenic sections showed extensive infiltration of red pulp cords and sinuses by leukemic cells with atrophy of the white pulp. These clinicopathologic features are similar to those described for patients with natural killer cell (NK)-LGL leukemia, whose cells are also CD56+. However, unlike NK-LGL leukemia, we could not show a direct pathogenic role for Epstein-Barr virus (EBV), as Southern-blot analyses using an EBV-joined termini probe were negative in these patients. Our findings suggest that CD3+, CD56+ LGL leukemia is a distinct clinicopathologic entity separate from the usual CD3+, CD56- T-LGL leukemia. The expression on leukemic LGL of CD56, an adhesion molecule, may determine the aggressive biologic nature of this newly described disease.
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PMID:CD3+, CD56+ aggressive variant of large granular lymphocyte leukemia. 754 72

Blood contact with synthetic surfaces during cardiopulmonary bypass (CPB) causes a diffuse inflammatory reaction that includes neutrophil activation. The purpose of this study was to determine if inhibition of neutrophil adhesion with a new antiinflammatory agent NPC 15669 (N-(9H-(2,7-dimethylfluorenyl-9-methoxy)-carbonyl)-L-leucine) could reduce pulmonary injury in a porcine model of CPB. NPC 15669 blocks adherence of activated neutrophils by inhibiting upregulation of the Mac-1 (CD11b/CD18) adhesion molecule. Sixteen piglets underwent 2 hours of hypothermic CPB followed by 2 hours of observation; 8 received NPC 15669 (10 mg/kg intravenous bolus followed by 6 mg.kg-1.h-1 intravenous infusion) and 8 received equal volumes of vehicle. After 90 minutes of CPB, expression of neutrophil adhesion molecule subunit CD18 increased 118% in control piglets but only 36% in piglets treated with NPC 15669 (p < 0.01). Although neutropenia developed in all animals during CPB, lung tissue myeloperoxidase content was significantly lower in treated than in control animals 2 hours after CPB (94.9 +/- 10.4 versus 46.9 +/- 5.5 mumol.10 mg-1.min-1; p < 0.002). Free radical-mediated lipid peroxidation (quantitated by spectrophotometric assay of plasma conjugated dienes) was significantly reduced by treatment with NPC 15669 during and after CPB. Pulmonary function was better in NPC 15669-treated animals: 2 hours after CPB, pulmonary vascular resistance increased 477% in control piglets but only 140% in piglets receiving NPC 15669 (p < 0.03); arterial oxygen tension was significantly greater in piglets receiving NPC 15669 (428 +/- 33 mm Hg) than in controls (141 +/- 46; p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of neutrophil adhesion during cardiopulmonary bypass. 790 44

Cardiopulmonary bypass (CPB) is known to cause complement and neutrophil activation, but the relative importance and interaction of these components in CPB-induced inflammation is unknown. In this study, a strain of dogs genetically deficient in the third component of complement (C3) was used to determine the contribution of C3 to neutrophil activation and pulmonary injury after CPB. Eleven dogs (5 C3-deficient and 6 controls) underwent 150 minutes of hypothermic CPB (28 degrees C) followed by 2 hours of observation. Before CPB, C3 levels were normal in controls and less than 1% of normal in C3-deficient dogs. In control dogs, functional activity of C3 decreased to 53.2% of baseline after 1 hour of CPB and there was immunohistochemical evidence of C3 deposition in lung after CPB; C3-deficient dogs had no C3 deposition in lung. Although similar degrees of neutropenia occurred during CPB in the two groups, expression of neutrophil adhesion molecule subunit CD18 was significantly lower in C3-deficient dogs than controls after 1 hour of CPB (45.9 +/- 3.7 versus 82.9 +/- 10.0 mean fluorescence units; p < 0.02). Postbypass lung tissue myeloperoxidase content was also less in C3-deficient dogs (43.8 +/- 4.6 versus 71.1 +/- 8.6 mumol x 10 mg-1 x min-1; p < 0.03). Cardiopulmonary bypass-associated lung injury (assessed by alveolar-arterial oxygen gradient, pulmonary vascular resistance, percent lung water, and light and electron microscopic appearance) was similar between groups. These results demonstrate that (1) C3 is deposited on pulmonary vascular endothelium during CPB and (2) C3 mediates increased expression of neutrophil CD18 and neutrophil sequestration in lung after CPB.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Complement and neutrophil activation during cardiopulmonary bypass: a study in the complement-deficient dog. 790 15

Neutrophils and macrophages play an important role in the body's microbicidal defense and have been implicated in the induction of tissue injury in reperfusion, endotoxemia and septic shock. Cellular host defense is accompanied by enhanced glucose use. In this study we examined the effect of monoclonal antibody 1F12 on in vivo glucose use by selected tissues and hepatic phagocytes. Monoclonal antibody 1F12 is specific for the CD18 adhesion molecule on rat neutrophils and is the only known antibody that induces profound neutropenia. The administration of monoclonal antibody 1F12 at a final dose of 2 mg/kg body weight enhanced the removal of neutrophils from the circulation within 15 min. Leukopenia was sustained for 24 hr. Large numbers of neutrophils were sequestered in the liver at 4 hr. Although the number of neutrophils in the liver at 24 hr after antibody treatment was lower than at 4 hr, these values were still higher than those in the saline controls. The rate of glucose metabolism by selected tissues was not significantly altered by the antibody, except by the liver, in which use increased 2.7-fold vs. the control value at 4 hr after treatment. Hepatocytes, endothelial cells and Kupffer cells contributed to the increase in the rate of glucose metabolism by the liver. The rate of glucose metabolism by Kupffer cells was significantly elevated at 4 and 24 hr, whereas the rate of glucose metabolism of hepatocytes and endothelial cells returned to normal at 24 hr. After antibody treatment, the glucose uptake by hepatic sequestered neutrophils was significantly reduced at 4 hr and returned to near-normal levels at 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monoclonal antibody against the CD18 adhesion molecule stimulates glucose uptake by the liver and hepatic nonparenchymal cells. 809 16

Human cytomegalovirus, HCMV, infects most of the population by adulthood; The primary infection is often accompanied by transient neutropenia and thrombocytopenia, and is followed by a period asymtomatic viral latency. In the setting of bone marrow transplantation, however, the immunosuppressed state of the recipient enables HCMV to re-activate or to infect the individual and cause serious sequelae. These range from hepatitis and gastrointestinal disease to interstitial pneumonia and hematologic abnormalities, which are more common in the allograft. Little is currently known about the mechanisms by which HCMV causes these hematologic abnormalities. In this review, we discuss experimental models which are helping investigators understand the immunology and pathology of CMV infection. We also summarize the vivo studies of the effects of HCMV on human hematopoiesis. Several possible mechanisms that could explain the deleterious effect of HCMV on human hematopoietic function include: 1) alteration of accessory cell function by inducing the production of inhibitory cytokines; 2) perturbation of stromal cell function resulting in a decreased production of hematopoietic factors or by altering cell surface adhesion molecule expression; 3) by direct infection of the hematopoietic stem or progenitor cells. It is likely that the pathogenesis of this syndrome is multifactorial therefore requiring a broad therapeutic approach. This would include the use of the antiviral agents, hematopoietic growth factors and donor derived HCMV specific cytolytic cells.
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PMID:Cytomegalovirus as a cause of pancytopenia. 872 2

The present study was designed to investigate the hypothesis that selective loss of peripheral blood CD45RO+ T lymphocytes in patients with chronic idiopathic neutropenia of adults (CINA), previously reported from our laboratory, may be due to enhanced extravasation into the tissues. Serum levels of endothelial cell-derived soluble cell adhesion molecules (sELAM, sICAM and sVCAM), usually used as indicators of endothelial cell activation, were measured in 73 CINA patients and 32 healthy volunteers using a micro-ELISA method. We found that patients had markedly elevated concentrations of all three soluble cell adhesion molecules studied compared to the controls, and serum levels of sELAM, sICAM and, more importantly, sVCAM correlated inversely with the numbers of both CD4+/CD45RO+ and CD8+/CD45RO+ T cell subsets. Using a micro-ELISA method, we also measured serum levels of two endothelial cell activators, interleukin (IL)-1beta and TNF-alpha, and found that CINA patients had significantly higher cytokine concentrations than control subjects. Serum levels of IL-1beta and TNF-alpha correlated positively with the values of all three soluble cell adhesion molecules and inversely with the numbers of CD4+/CD45RO+ and CD8+/CD45RO+ T cell subsets. Moreover, we measured serum levels of the chemokine RANTES by a micro-ELISA technique and found that CINA patients also had elevated concentrations of the molecule compared to controls. Serum RANTES correlated positively with IL-1beta, TNF-alpha, sICAM, sVCAM and sELAM and inversely with the numbers of both CD4+/CD45RO+ and CD8+/CD45RO+ T cell subsets. These findings strongly suggest that CINA patients have an activated endothelium to which CD45RA+ and CD45RO+ T cells tether and roll, but firm adhesion and transendothelial migration are restricted to CD45RO+ T cell subsets, as endothelial VCAM-1 interacts with the vascular leukocyte adhesion molecule-4 (VLA-4) constitutively expressed on CD45RO+ but not on CD45RA+ T cells. Subsequent subendothelial and tissue migration of CD45RO+ T cells may be facilitated by the chemokine RANTES, which acts mainly on CD45RO+ T cells. We concluded that selective loss of peripheral blood CD45RO+ T lymphocytes in CINA patients is probably due, at least in part, to enhanced extravasation of both CD4+/CD45RO+ and CD8+/CD45RO+ T cell subsets into the tissues.
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PMID:Selective loss of peripheral blood CD45RO+ T lymphocytes correlates with increased levels of serum cytokines and endothelial cell-derived soluble cell adhesion molecules in patients with chronic idiopathic neutropenia of adults. 982 46

We have previously demonstrated an increase in the adhesion molecule lymphocyte function-associated antigen-1 (LFA-1) in GVHD after small bowel transplantation (SBTx) and a therapeutic effect for the monoclonal antibody (MoAb) to LFA-1 in the same model. The present study evaluated the role of MoAb to LFA-1's ligand, intercellular adhesion molecule-1 (ICAM-1) in GVHD. Methods. GVHD was created in LBNF1 rats by heterotopic vascularized SBTx from Lewis donors. Saline treated SBTx-GVHD and sham-operated control animals were compared to animal groups treated with MoAb to ICAM-1 or MoAb to ICAM-1 and LFA-1. GVHD was evaluated by measuring spleen index, white blood cell count, bowel permeability, weight loss, and animal survival. RESULTS. Animals treated with the MoAb to ICAM-1 appeared clinically to have almost as severe GVHD as untreated animals; however, they had improved spleen indices, less neutropenia and weight loss, and survived longer than untreated animals (range 15-22 days in treated animals vs 12-16 days in untreated animals, P < 0. 01). Treatment with MoAb to both ICAM-1 and LFA-1 appeared to have a synergistic beneficial effect on GVHD (range 19-29 days, P < 0.001 vs untreated animals). Conclusion. MoAb to ICAM-1 alone or in combination with MoAb to LFA-1 ameliorates GHVD after SBTx and prolongs survival.
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PMID:Amelioration of graft versus host disease with anti-ICAM-1 therapy. 987 25

The etiology of drug-induced agranulocytosis is poorly understood. Many drugs that induce neutropenia or agranulocytosis can be metabolized to reactive intermediates that covalently bind to macromolecules. Until now, the myeloid precursor cell or an earlier committed progenitor cell has been favoured as the target for toxicity, due to evidence in some cases of cytotoxic action or antibodies against neutrophils. In the bone marrow, where neutrophils mature, certain components of the stromal microenvironment, e.g. intracellular adhesion molecule 1, vascular cell adhesion molecule 1, CD11b/CD18, heparan sulfate proteoglycans, fibronectin and hemonectin are essential for normal myeloid maturation. This article proposes that drugs implicated in agranulocytosis, or more likely their reactive metabolites, interact with specific components of the extracellular matrix and interfere with the normal regulation of granulopoiesis.
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PMID:Drugs that induce neutropenia/agranulocytosis may target specific components of the stromal cell extracellular matrix. 1053 10

Because neutropenia may aggravate infections in alcoholics, effects of ethanol on the generation of myeloid growth factors by human umbilical vein endothelial cells (HUVECs) and on interactions with neutrophils were examined in vitro. Exposure of HUVECs to ethanol (0.01%-1%) dose-dependently inhibited (by 12%-27%) the release of stem cell factor, granulocyte-macrophage and granulocyte colony-stimulating factors (CSFs), or interleukin (IL)-8, but not of macrophage CSF triggered by lipopolysaccharide (LPS) or IL-1. Ethanol also inhibited the LPS-induced increase in HUVECs to bind neutrophils by 28% (without affecting the expression of intracellular adhesion molecule-1 and E-selectin) and inhibited the translocation of the p65 subunit of NF-kappaB from the cytoplasm to the nucleus by 46%. Thus, exposure of HUVECs to ethanol inhibited the generation of cytokines important for myeloid cell development and reduced the adhesiveness of HUVECs for neutrophils: effects that are possibly linked to the reduced activation of NF-kappaB.
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PMID:Effects of ethanol on NF-kappaB activation, production of myeloid growth factors, and adhesive events in human endothelial cells. 1151 38


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