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 investigated cellular responses in a rabbit to i.v. administration of five established chemotactic factors (leukotriene B4 (LTB4), platelet-activating factor (PAF), C5a, N-Formyl-Met-Leu-Phe (F-MLF), and IL-8), and each exerted a characteristic effect on circulating white blood cell levels. All five factors induced a rapid and transient leukopenia. The blood was nearly devoid of circulating neutrophils 5 min after administration of each chemotactic factor. Other leukocytes were also variably depleted during the leukopenic phase, including eosinophils, basophils, monocytes, and lymphocytes. The lymphocyte numbers remained significantly depressed (approximately 30%) for as long as 3 h after administration of PAF or f-MLF. Each chemotactic factor produced a marked neutrophilia (i.e., 250-400% of baseline levels) after the initial leukopenia. Eosinophil numbers were elevated along with the neutrophil response in the C5a- and LTB4-treated animals. Basophil levels were significantly elevated only in LTB4-treated animals. The cellular response to PAF, f-MLF, and IL-8 appeared to be specific for the neutrophils. The kinetic profiles of the neutrophilia induced by PAF (10 micrograms/kg) or f-MLF (2.5 micrograms/kg) were similar, with maximal responses occurring 3 to 4 h after administration. In contrast, LTB4 (10 micrograms/kg), IL-8 (2.5 micrograms/kg), and C5a (5 micrograms/kg) induced a more rapid neutrophilia, with peak responses occurring 1 to 1.5 h after injection, and remaining elevated for 3 to 4 h. In all animals the neutrophilia was accompanied by a relative increase in the number of nonsegmented neutrophils (bands), suggesting that a major component of leukocytosis is caused by the release of bone marrow reserves. Phenidone (10 mg/kg), a dual cyclooxygenase/5-lipoxygenase inhibitor, affected neither the neutropenia nor the neutrophilia induced by C5a, f-MLF, or PAF. The protein synthesis inhibitor actinomycin D also failed to suppress neutrophil responses induced by either C5a or PAF. These results suggest that leukocytosis is a common response induced by all neutrophil chemotactic factors. Leukocytosis appears to be a direct result of the dynamic adaptive response of neutrophils to chemotactic factor stimulation without involvement of a secondary mediator system.
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PMID:Neutrophil chemotactic factors promote leukocytosis. A common mechanism for cellular recruitment from bone marrow. 131 Jul 8

A hyperdynamic sepsis model was set up in seven adult baboons to evaluate neutrophil-activating peptide-1/interleukin (IL)-8 (NAP-1/IL-8), IL-1 beta, IL-6, tumor necrosis factor-alpha (TNF alpha), and IFN-gamma in plasma. By continuous intravenous administration of 10(10) cfu/kg live Escherichia coli over 8 h with additional infusion therapy (less than or equal to 50 ml/kg/h), endotoxin plasma levels of 2.7-22.3 ng/ml were observed. In plasma the kinetics of NAP-1/IL-8 and IL-6 were similar to those of IL-1 at the end of the experiment (8 h) (peak median values, 34, 4197, and 230 ng/ml, respectively). Differences were greatest for IL-6. Monocyte activation during sepsis was confirmed by elevated plasma neopterin levels (91-139 mumol/mmol of creatine). Granulocyte activation was evident from both incipient neutropenia and the massive release of neutrophil elastase into the plasma as measured by a new immunoassay (peak level, 374 ng/ml). Thus, in primate bacteremia, early TNF release is followed by a concomitant increase of NAP-1/IL-8 with plasma kinetics similar to those of IL-6 and IL-1 and accompanied by massive activation of neutrophils.
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PMID:Plasma neutrophil-activating peptide-1/interleukin-8 and neutrophil elastase in a primate bacteremia model. 190 12

Much effort has been directed toward elucidating the host response to sepsis and inflammation, resulting in the definition of a cascade of endogenous mediators that direct metabolic and immunological responses. Here we report that IL-8, a novel cytokine produced by a variety of cells in vitro in response to stimulation with bacterial LPS and the proinflammatory cytokines, appears in the circulation of primates in vivo during septic shock, sublethal endotoxemia, and after the administration of IL-1 alpha. The magnitude of the IL-8 response correlates with the severity of the insult, and levels of IL-8 peak relatively late, after those of TNF-alpha and IL-1 beta, and simultaneously with those of IL-6. IL-8 has been primarily defined as a selective activator and chemoattractant of neutrophils, and we demonstrate that after LPS or IL-1 alpha infusion, circulating neutrophil numbers rapidly recover from an initial neutropenia while IL-8 concentrations are maximal, supporting the hypothesis that IL-8 influences circulating leukocyte populations in vivo. We conclude that IL-8 is another participant in the cytokine cascade elicited by sepsis and inflammation and, as such, may play a significant role in host defense and disease.
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PMID:IL-8 in septic shock, endotoxemia, and after IL-1 administration. 202 76

In this paper we describe the case of a 16-year-old boy with childhood onset cyclic neutropenia (CN) with a 21 d cycle who was successfully treated with recombinant granulocyte-colony stimulating factor (G-CSF). Cyclic therapy with G-CSF (5 micrograms/kg/d s.c. for 1 week every 21 d) maintained peripheral neutrophil count above the normal range, reduced the incidence of severe infections and significantly improved the patient's performance status throughout an 18-month follow-up. Phenotypic analysis of circulating lymphocytes demonstrated that G-CSF treatment does not modify the phenotypic profile of circulating B, T and NK cell populations. Circulating neutrophils released normal amounts of cytokines (including IL-1 beta, IL-8, TNF alpha) and superoxide anion during G-CSF therapy.
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PMID:Childhood onset cyclic neutropenia: G-CSF therapy restores neutrophil count but does not influence superoxide anion and cytokine release by neutrophils. 753 83

Plasma levels of IL-1, IL-6, IL-8, IL1-RA, TNF alpha, and G-CSF were prospectively studied during 23 chemotherapy cycles of 20 patients suffering from acute myelogenous leukemia. Increased plasma levels of IL-6, IL-8, and G-CSF were observed in patients with febrile neutropenia and/or major infection. Plasma levels of IL-6, IL-1, TNF alpha and IL-1-RA measured 1 day before and 1 day after the onset of febrile episodes did not accurately predict the development of major infection. In contrast, IL-8 plasma levels were significantly higher in those patients who subsequently developed major infection. The question whether IL-8 plasma levels identify high risk or low risk patients with sufficient specificity and sensitivity has to be answered in large scale clinical trials.
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PMID:Plasma levels of IL-1, TNF alpha, IL-6, IL-8, G-CSF, and IL1-RA during febrile neutropenia: results of a prospective study in patients undergoing chemotherapy for acute myelogenous leukemia. 757 21

A phase IIb trial using liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in combination with ifosfamide (IFX) for patients with relapsed osteosarcoma was undertaken to determine (a) the tolerability of the combination therapy, (b) if L-MTP-PE increased the toxicity of IFX, and (c) whether IFX altered or suppressed the in vivo immune response to L-MTP-PE. Patients had histologically proven osteosarcoma and pulmonary metastases that either developed during adjuvant chemotherapy or were present at diagnosis, persisted despite chemotherapy, and recurred following surgical excision. Stratum A patients were rendered clinically free of disease within 4 weeks of study entry prior to receiving combination therapy. IFX was administered at 1.8 g/m2 for 5 days every 21 days for up to eight cycles. L-MTP-PE was administered twice weekly for 12 weeks, then once weekly for 12 weeks. Once cycle of combination therapy was defined as 5 days of IFX and 3 weeks of L-MTP-PE therapy. Stratum B patients had measurable disease at study entry that was judged to be amenable to surgical resection. Stratum B patients received three cycles of combination therapy prior to surgery to judge clinical and histologic response. Postoperatively, patients received an additional five cycles. A total of nine patients were entered into the protocol: six on stratum A and three on stratum B. Serial blood samples were collected and assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha], interleukin-6 [IL-6], IL-8, neopterin, C-reactive protein). In addition, peripheral blood monocyte tumoricidal activity was evaluated pre- and post-combination therapy. Complete blood counts with differential and platelet counts were followed weekly. No increase in the toxic side effects of IFX was demonstrated when administered with L-MTP-PE nor were delays in IFX administration due to neutropenia experienced. The toxic side effects of L-MTP-PE were also not increased. Elevations of serum C-reactive protein, plasma neopterin, IL-6, IL-8, and TNF alpha following combination therapy were similar to those observed in patients treated with L-MTP-PE alone. Monocyte-mediated tumoricidal activity was elevated 24 and 72 h following L-MTP-PE and IFX therapy, similar to what has been reported following L-MTP-PE alone. Tumor specimens obtained from stratum B patients showed the histologic characteristics consistent with a "chemotherapy effect," i.e., dead, amorphous, acellular osteoid with cell drop-out.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Combination therapy with ifosfamide and liposome-encapsulated muramyl tripeptide: tolerability, toxicity, and immune stimulation. 761 44

Pulmonary dysfunction caused by pulmonary neutrophil sequestration is a frequent postoperative complication in patients undergoing cardiopulmonary bypass (CPB) surgery. It is yet unclear whether treatment with corticosteroids in vivo in these patients can prevent complement-mediated neutrophil activation and sequestration in the lungs. Therefore, we conducted a prospective study in order to investigate whether methylprednisolone (MP) pretreatment (30 mg/kg) could influence the appearance of IL-8 (a recently discovered cytokine with potent neutrophil-chemotactic activity) in the peripheral circulation. We also studied the effects of MP pretreatment on the inflammatory parameters in the bronchoalveolar lavage (BAL) fluid 4 h postoperatively. Although peripheral neutropenia and the rise in IL-8 serum levels was less pronounced in MP-treated than in non-steroid-treated patients, there was no significant difference in albumin, total protein, concentrations of IL-8 and C3a, and the number of neutrophils in the BAL fluid between the two groups. However, when cultured in vitro, alveolar macrophages from patients treated with MP released significantly lower IL-8, both in basal conditions and after stimulation with lipopolysaccharide. Our results show that MP does not prevent (IL-8-mediated) pulmonary neutrophil infiltration after CPB, although it might affect certain aspects of the microvascular lung injury.
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PMID:Interleukin-8 production in patients undergoing cardiopulmonary bypass. The influence of pretreatment with methylprednisolone. 821 44

The activity of the steroid-inducible protein lipocortin-1 (LC1; with a primary sequence of 346 amino acids; also called annexin 1), a fragment corresponding to amino acids 1-188 and a short peptide from the N-terminus (amino acid 2-26) were tested for anti-inflammatory actions in three models of acute inflammation in the mouse in comparison with a mAb anti-CD11b (alpha CD11b). In the mouse air-pouch model LC1, fragment 1-188 and peptide Ac2-26 exhibited powerful inhibitory effects (ED50 approximately 5.2, 38 and 88 micrograms/mouse, respectively) on leukocyte migration elicited by IL-1. LC1 was approximately 200 times more potent than Ac2-26 on a molar basis although both gave maximal inhibitions, in contrast fragment 1-188 only produced a partial dose-response curve. LC1 was approximately 20 times more potent on a molar basis in this assay than the alpha CD11b mAb. Peptide Ac2-26 and the mAb alpha CD11b also blocked cell migration into the air-pouch induced by IL-8 with approximately the same potency. In the mouse skin edema and zymosan peritonitis assays Ac2-26 was inhibitory (ED50 of 200 micrograms/mouse) but less so than the alpha CD11b antibody (ED50 approximately 0.5 mg/mouse). Both LC1 (10 micrograms) and Ac2-26 (200 micrograms) completely blocked FMLP-induced neutropenia in the mouse. Studies using an inactivated LC1 preparation, which binds to the same high affinity binding sites as the biologically active material, indicated that the short peptide acts on the same sites as the native LC1. This study confirms the activity of LC1 in another model of experimental inflammation and suggests that it acts partly through inhibition of leukocyte activation with an overall effect qualitatively comparable to the blocking of CD11b portion of a beta 2-integrin complex. It also shows that peptides derived from the N-terminal domain of LC1 may mimic the activity of the full length molecule and points the way for a new family of anti-inflammatory substances that inhibit leukocyte trafficking.
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PMID:Lipocortin-1 fragments inhibit neutrophil accumulation and neutrophil-dependent edema in the mouse. A qualitative comparison with an anti-CD11b monoclonal antibody. 840 3

Interleukin-8 (IL-8) is a chemoattractant cytokine involved in chemotaxis and activation of neutrophils. Because in vivo administration of IL-8 induces mobilization of hematopoietic stem cells in mice, we assessed the mobilizing properties of IL-8 in rhesus monkeys. Recombinant human IL-8 was administered as a single intravenous injection at doses of 10, 30, and 100 micrograms/kg to rhesus monkeys (age, 2 to 3 years; weight, 2.5 to 4.5 kg). Venous blood samples were obtained at time intervals ranging from 1 to 480 minutes after IL-8 administration. Cell counts, colony-forming unit-Mix assays, and fluorescence-activated cell sorter analysis were performed. Plasma was harvested to assess IL-8 levels. A time-controlled bolus intravenous injection of 100 micrograms IL-8 per kilogram of body weight resulted in peak IL-8 plasma levels up to 5 micrograms/mL. The calculated half-time life of free IL-8 was 9.9 +/- 2.2 minutes. IL-8 injection resulted in instant neutropenia that was due to pulmonary sequestration, as shown using 99mTc-labeled leukocytes. Within 30 minutes after IL-8 injection, neutrophilia developed with counts up to 10-fold greater than baseline levels. The numbers of hematopoietic progenitor cells (HPCs) increased from 45 +/- 48/mL to 1,382 +/- 599/mL of blood at 30 minutes after injection of 100 micrograms IL-8 per kilogram of bodyweight (mean +/- SD, n = 8). Individual animals showed 10- to 100-fold increase in numbers of circulating HPCs that returned to almost pretreatment values (92 +/- 52 CFU/mL) at 240 minutes after the injection of IL-8. Immunophenotyping showed no significant changes in lymphocyte (sub)populations. A second bolus injection of IL-8 with an interval of 72 hours resulted in similar numbers of mobilized stem cells as observed after the first injection, showing that no tachyphylaxis had occurred. We conclude that IL-8 induces mobilization of HPCs from the bone marrow of rhesus monkeys in a rapid and reproducible fashion. Therefore, IL-8 may be a potentially useful cytokine in the setting of blood stem cell transplantation.
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PMID:Rapid mobilization of hematopoietic progenitor cells in rhesus monkeys by a single intravenous injection of interleukin-8. 855 3

Macrophage colony-stimulating factor (M-CSF) was found to be a glycoprotein with a molecular weight of 85 kDa which stimulated macrophage colony formation of mouse bone marrow cells in a semisolid agar culture system in 1978. M-CSF stimulates differentiation of progenitor cells to mature monocytes, and prolongs the survival of monocytes. It enhances expression of differentiation antigens and stimulates chemotactic, phagocytic and the killing activities of monocytes. Macrophage CSF also stimulates production of several cytokines such as granulocyte-macrophage CSF, granulocyte CSF and interleukin (IL)-6 by priming monocytes, and directly stimulates production and secretion of IL-8 and reactive nitrogen intermediates. In addition to the stimulation of hematopoiesis, M-CSF also stimulates differentiation and proliferation of osteoclast progenitor cells and cytotrophoblasts. Proteoglycan type M-CSF, which contains chondroitin sulfate chains, was found in 1992. In a large-scale double-blind controlled study on acute myeloid leukemia (AML), it has been shown that the administration of M-CSF to patients after consolidation chemotherapies shortens the periods of neutropenia and thrombopenia after chemotherapy and reduces the incidence and shortens the duration of febrile neutropenia, as well as shortening the period required to finish three courses of intensive consolidation therapy.
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PMID:Biological activities and clinical application of M-CSF. 963 77


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