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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infusion of activated plasma induces neutropenia and sequestration of neutrophils within the microvasculature. This study examined the role of the adhesion glycoprotein complex, CD11/CD18, in this sequestration. Rabbits pretreated with either the anti-CD18 monoclonal antibody (mAb) 60.3 or saline were given infusions of zymosan-activated plasma (ZAP) or saline. The effect of mAb 60.3 on the changes in circulating neutrophil counts, radiolabeled neutrophil kinetics in the lung, and the pulmonary microvascular accumulation of neutrophils induced by ZAP infusion was determined. The data show that pretreatment with mAb 60.3 did not inhibit either the rate of onset or the severity of the neutropenia but prevented the sustained neutropenia. In addition, mAb 60.3 completely prevented the ZAP-induced changes in radiolabeled neutrophil kinetics and largely inhibited the accumulation of neutrophils within the capillaries and the small vessels when evaluated after 15 min of ZAP infusion. We conclude that neutrophil accumulation is a two-step process, the first occurring through a CD18-independent mechanism that may involve a stimulus-induced decrease in neutrophil deformability and acts to slow neutrophil transit through the lung. The second step requires CD18-dependent adhesion and is needed for prolonged accumulation of neutrophils within the pulmonary microvasculature.
Am J Respir Cell Mol Biol 1992 Aug
PMID:The role of CD18-mediated adhesion in neutrophil sequestration induced by infusion of activated plasma in rabbits. 135 74

Plasma lactoferrin content was measured before and after therapy with recombinant granulocyte-macrophage colony-stimulating factor in five patients with aplastic anaemia, six with myelodysplasia, and three with prolonged, severe, chemotherapy-induced neutropenia. Before therapy plasma lactoferrin content was uniformly low. However, patients with aplastic anemia and those with chemotherapy-induced neutropenia had a normal lactoferrin:neutrophil ratio. The low levels of plasma lactoferrin thus reflected the low granulocyte mass. On the other hand, patients with myelodysplasia also had reduced lactoferrin:neutrophil ratios, suggesting qualitative/quantitative abnormalities of neutrophil lactoferrin production. After treatment with granulocyte-macrophage colony-stimulating factor, plasma lactoferrin levels increased in patients with aplastic anemia and in those with chemotherapy-induced neutropenia who showed a neutrophil response to treatment. In these patients, the lactoferrin:neutrophil ratio became elevated, suggesting increased synthesis/release of lactoferrin from neutrophils. However, patients with myelodysplasia continued to show depressed lactoferrin:neutrophil ratios, even when there had been an increase in granulocyte count, suggesting persistent abnormalities of neutrophil lactoferrin production/release. The implications of these findings for treatment of neutropenic patients with granulocyte-macrophage colony-stimulating factors are discussed.
Mol Biother 1992 Jun
PMID:Plasma lactoferrin content in neutropenic patients: effects of treatment with recombinant granulocyte-macrophage colony-stimulating factor. 151 94

We have evaluated the effect of Interleukin-2 [IL-2] after Cyclophosphamide (C) chemotherapy in 41 patients with metastatic cancer. IL-2 was given as a continuous infusion priming cycle 36 hours after C at 1 gm/m2 intravenously. In 39 evaluable patients, there were no complete remissions [CR], 2 partial remissions [PR], and 1 had a minor response [MR]. Stable disease for 30 days was seen in 16 patients whereas 20 progressed. The durations of partial and minor responses were brief, ranging from 1-6 months. Grade 3-4 neutropenia was seen in 41%. This was more severe than seen with IL-2 alone or IL-2 combined with lower doses of C. The marrow suppression was due to the chemotherapy. This combination of IL-2 and C appears to be reasonably well tolerated by patients, but toxicity is greater and the response rate is no better than results achieved by IL-2 alone. Responses of 26 patients with renal cancer appear to be inferior to our historical data using IL-2/LAK cells without C. Immune monitoring demonstrated changes expected with C chemotherapy (i.e., a non-selective decline in immune function). C induced no further differences in IL-2 induced changes in immune function.
Mol Biother 1991 Jun
PMID:Continuous infusion of interleukin-2 and cyclophosphamide as treatment of advanced cancers: a National Biotherapy Study Group Trial. 191 Jun 23

The in vivo effect of the lipophilic muramyl peptide MTP-PE on the proliferation of blood cells and various tissues of the rabbit was studied by means of 3H-thymidine. Animals were killed up to 120 h after one or two i.v. injections of MTP-PE (10 mg/kg). MTP-PE caused a drastic effect on white blood cells: (1) neutropenia and lymphocytopenia occurring within 5 h was followed by leukocytosis of neutrophils and their juvenile forms by 24 h and thereafter, (2) within 24 h the number of prelabelled, i.e. recently regenerated, mononuclear cells in the bone marrow and the vascular system of various tissues increased approximately threefold, and (3) within 48 h the concentration of proliferating monocytic cells (1-h pulse labelling) rose to maximum levels of up to 20-fold in the lumina of blood vessels, particularly in capillaries of many organs. The number of proliferating cells also increased in the adventitia of medium and small arteries with a maximum at 48 h, whereas this occurred only later in the media and hardly at all in the intima. Thus, these proliferating, apparently monocytic cells are blood derived, and migrate into the tissue within 24 h after MTP-PE administration. In addition, proliferation in the epithelium of the bile ducts and oesophagus was also stimulated with a maximum at 24 h after MTP-PE. In contrast, enhanced proliferation occurred more slowly and to a lesser extent in hepatocytes, hepatic interstitial cells, and renal epithelial cells, consistent with a regenerative process after an inflammatory or toxic event.
Virchows Arch B Cell Pathol Incl Mol Pathol 1988
PMID:Stimulation of cell proliferation in rabbits by MTP-PE, a lipophilic muramyl peptide. 289 30

Neonatal sepsis is a major cause of morbidity and mortality in newborn infants. Hematopoiesis and host defense in the neonate is developmentally immature compared with the adult. Defects in both the quantitative and qualitative aspects of the phagocytic system contribute significantly to a relative state of immunodeficiency in the neonate. Dysregulation of neonatal hematopoiesis and the immune response is a significant contributing factor to the increased susceptibility of the neonate to infection. A relatively small set of pluripotent stem cells gives rise to large numbers of functionally diverse mature effector cells. Cell proliferation and differentiation are regulated and controlled by highly specific protein factors, affecting single and multiple lineage hematopoiesis. Reduced neonatal rat myeloid progenitor pools, accelerated myeloid progenitor proliferative rates and decreased total body neutrophil storage pools predispose the newborn rat to depletion of mature effector neutrophils and a tendency to develop neutropenia during states of increased demand such as overwhelming bacterial infection. We review here the multifactorial complex biological process involved in the regulation of hematopoietic growth factors. We also review the biological effects of various non-lineage-committed and lineage-committed growth factors as reported in in vitro investigations and in vivo neonatal animal experiments. We also review our results of phase I/II clinical studies utilizing rhuG-CSF in neonates with presumed sepsis, and of rhuGM-CSF in very low birth weight neonates.
Cytokines Mol Ther 1995 Sep
PMID:The role of cytokines in modulating neonatal myelopoiesis and host defense. 938 73

The effects of intravenous injection of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on circulating neutrophil numbers, pulmonary vascular permeability, and morphologic changes in the lung were examined in rabbits. Intravenous injection of rhG-CSF caused a rapid, profound neutropenia due to neutrophil sequestration primarily within capillaries but also in larger microvessels of the lungs. Examination of neutrophil deformability using microfilters revealed that granulocyte colony-stimulating factor (G-CSF) treatment caused a rapid stiffening of neutrophils through the polymerization of F-actin but not microtubule assembly. The expression of CD11b, CD11c, and CD18 on human neutrophils after G-CSF treatment increased, but CD11a did not. Intravenous injection of rhG-CSF did not induce neutrophil emigration or albumin leakage into alveolar space, wet/dry lung weight ratios were unchanged, and no pathologic changes in lung histology were observed. These studies indicate that injection of rhG-CSF caused a rapid neutropenia and neutrophil sequestration in the lungs that is likely to be mediated through a G-CSF-induced decrease in neutrophil deformability, although neutrophil-endothelial cell adhesion may also play a role. However, this G-CSF-induced neutrophil sequestration did not induce a massive lung injury.
Am J Respir Cell Mol Biol 1998 Jul
PMID:Granulocyte colony-stimulating factor induces neutrophil sequestration in rabbit lungs. 965 Nov 93

Most chemotherapy agents function by causing damage to the DNA of rapidly dividing cells, such as those in the bone marrow, leading to anemia and leukopenia during chemotherapy and the development of secondary leukemias in the years following recovery from the original disease. We created an animal model of nitrosourea-based chemotherapy using ethylnitrosourea (ENU) to investigate the effect of niacin deficiency on the side effects of chemotherapy. Weanling Long-Evans rats were fed diets containing various levels of niacin for a period of 4 weeks. ENU treatment started after 1 week of feeding and consisted of 12 doses delivered by gavage, every other day. Cancer incidence was also monitored in the following months. ENU treatment caused many of the acute symptoms seen in human chemotherapy patients, including anemia and neutropenia. Niacin deficiency (ND) had several interesting effects, alone and in combination with ENU. Niacin deficiency alone caused a modest anemia, while in combination with ENU it induced a severe anemia. Niacin deficiency alone caused a 4-fold increase in circulating neutrophil numbers, and this population was drastically reduced by ENU-treatment. In the long term, macin deficiency caused an increased incidence of cancer, especially chronic granulocytic leukemias.
Mol Cell Biochem 1999 Mar
PMID:Niacin deficiency increases the sensitivity of rats to the short and long term effects of ethylnitrosourea treatment. 1033 42

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by variable degrees of oculocutaneous albinism, easy bruisability, and bleeding as a result of deficient platelet dense bodies, and recurrent infections, with neutropenia, impaired chemotaxis and bactericidal activity, and abnormal NK cell function. Neurologic involvement is variable, but often includes peripheral neuropathy. Most patients also undergo an "accelerated phase," which is a nonmalignant lymphohistiocytic infiltration of multiple organs resembling lymphoma. Death often occurs in the first decade from infection, bleeding, or development of the accelerated phase. The hallmark of CHS is the presence of huge cytoplasmic granules in circulating granulocytes and many other cell types. These granules are peroxidase-positive and contain lysosomal enzymes, suggesting that they are giant lysosomes or, in the case of melanocytes, giant melanosomes. The underlying defect in CHS remains elusive, but the disorder can be considered a model for defects in vesicle formation, fusion, or trafficking. Because the beige mouse demonstrates many characteristics similar to those of human CHS patients, including dilution of coat color, recurrent infections, and the presence of giant granules, it is considered the animal homologue of CHS. The beige gene, Lyst, was mapped and sequenced in 1996, prompting identification of the human LYST gene on chromosome 1q42. Lyst and LYST show 86.5% sequence homology. LYST encodes a 429 kDa protein with a function that remains unknown, but the source of extensive speculation among students of cell biology.
Mol Genet Metab 1999 Oct
PMID:Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome. 1052 80

Mucositis, the inflammation and necrosis of mucosal membranes, is a serious and debilitating consequence of many cancer therapies. We were interested in the potential role of filgrastim (recombinant methionyl human granulocyte colony-stimulating factor, r-metHuG-CSF) in the reduction of mucositis. Patients with newly diagnosed small-cell lung cancer (SCLC) were treated with CAE chemotherapy (cyclophosphamide, doxorubicin, and etoposide) and placebo or filgrastim. If patients had an episode of febrile neutropenia, they received unblinded filgrastim in subsequent CAE cycles. Oral mucositis was considered to have occurred if a patient reported any clinical sign or symptom of oral mucositis with or without oral candidiasis. Oral mucositis was analyzed using the unadjusted chi-square test, and time to first episode of mucositis was analyzed using the stratified log-rank test as well as the Cox proportional hazards regression model. During cycle 1, placebo-treated patients had more episodes of mucositis (47%) compared with those patients randomized to filgrastim (28%). Across all cycles of treatment, 70% of placebo-treated patients experienced mucositis, compared with 53% of patients randomized to filgrastim. A significant reduction in the incidence of chemotherapy-related oral mucositis occurred across multiple cycles of treatment in patients treated with filgrastim.
Cytokines Cell Mol Ther 1999 Dec
PMID:Reduction of oral mucositis by filgrastim (r-metHuG-CSF) in patients receiving chemotherapy. 1085 Mar 81

Clozapine, an atypical antipsychotic used in the treatment of refractory schizophrenia, causes neutropenia and agranulocytosis in 3 and 0.8% of patients, respectively. Clozapine undergoes bioactivation to a chemically reactive nitrenium ion, which has been shown to cause neutrophil cytotoxicity. To define further the mechanism of cell death, we have investigated the toxicity of clozapine, its stable metabolites, and its chemically reactive nitrenium ion to neutrophils and lymphocytes. Clozapine was able to induce neutrophil apoptosis at therapeutic concentrations (1-3 microM) only when it was bioactivated to the nitrenium ion. The parent drug caused apoptosis at supratherapeutic concentrations (100-300 microM) only. Neutrophil apoptosis induced by the nitrenium ion, but not by the parent drug itself, was inhibited by antioxidants and genistein and was accompanied by cell surface haptenation (assessed by flow cytometry) and glutathione depletion. Dual-color flow cytometry showed that neutrophils that were haptenated were the same cells that underwent apoptosis. No apoptosis of lymphocytes was evident with the nitrenium ion or the parent drug, despite the fact that the former caused cell surface haptenation, glutathione depletion, and loss of membrane integrity. Demethylclozapine, the major stable metabolite in vivo, showed a profile that was similar to, although less marked than that observed with clozapine. N-oxidation of clozapine or replacement of the nitrogen (at position 5) by sulfur produced compounds that were entirely nontoxic to neutrophils. In conclusion, the findings of the study expand on potential mechanisms of clozapine-induced cytotoxicity, which may be of relevance to the major forms of toxicity encountered in patients taking this drug.
Mol Pharmacol 2000 Jul
PMID:Induction of metabolism-dependent and -independent neutrophil apoptosis by clozapine. 1086 Sep 43


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