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 purpose of this study was to characterize the role of tumour necrosis factor (TNF) and neutrophils (PMN) in the pathogenesis of pulmonary oedema induced by endotoxin (lipopolysaccharide (LPS)). Intraperitoneal administration to BALB/c mice of 0.6-1 mg of LPS caused pulmonary oedema and lethality. This was associated with production of TNF in serum and bronchoalveolar lavage fluid and with accumulation of PMN in the lung. In this experimental model, we could block TNF production by different means: pretreatment 30 min before LPS with 4 mg/kg of i.p. chlorpromazine (CPZ), 3 mg/kg of i.p. dexamethasone (DEX), 1 g/kg p.o. of N-acetylcysteine (NAC, an antioxidant precursor of glutathione), or an anti-TNF MoAb. CPZ, DEX and anti-TNF completely prevented LPS lethality but not pulmonary oedema or pulmonary PMN infiltration, indicating that: (i) lung oedema is not the main cause of death after LPS; and (ii) lung oedema induced by LPS is not mediated by TNF. Pretreatment with NAC not only inhibited TNF production but also protected against LPS-induced pulmonary oedema, indicating that reactive oxygen intermediates are implicated. NAC also blocked TNF production in blood and in bronchoalveolar lavage. We also tested the effect of PMN depletion induced with cyclophosphamide (CP) or 5-fluorouracil (5-FU). While no pulmonary PMN infiltrate was observed in PMN-depleted mice, neutropenia did not prevent LPS lethality or oedema, indicating PMN do not play an important role in the toxic effects of LPS in this experimental model.
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PMID:Role of tumour necrosis factor and reactive oxygen intermediates in lipopolysaccharide-induced pulmonary oedema and lethality. 844 68

The following substances were tested for their influence on granulocyte function: 8 sera that contained human granulocyte-specific alloantibodies against the antigens NA1, NA2 and NB1, two HLA antisera, and the monoclonal antibodies W6/32 and CLB-FcR-gran 1. The effects examined included spontaneous and directed migration, immune phagocytosis inhibition and the generation of oxygen radicals. Using the under-agarose technique, spontaneous migration of sensitized granulocytes was normal. For all antibodies tested, the chemotactic index for N-fMLP, LTB4 and opsonized zymosan was greater than 1. Granulocyte immune phagocytosis of sensitized sheep red blood cells was strongly inhibited by all alloantisera and monoclonal antibodies. The generation of oxygen radicals after triggering the respiratory burst with sensitized sheep red blood cells was also strongly inhibited in the chemiluminescence assay. Immune phagocytosis and chemiluminescent response of granulocytes lacking the corresponding antigen of the tested alloantibodies were not affected. Since sensitization of neutrophils with F(ab')2 fragments of the monoclonal antibodies W6/32 and CLB-FcR-gran 1 showed lower inhibition of generation of oxygen radicals after triggering, Fc-dependent interaction with the target cells seems to be necessary for inhibition. Our results suggest that binding of NA1-, NA2- or NB1-specific alloantibodies to granulocytes not only causes neutropenia, but also impairs granulocyte function.
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PMID:Influence of granulocyte antibodies on granulocyte function. 851 50

Polymorphonuclear neutrophils play an important role against pathogens through the production of toxic oxygen metabolites by the NADPH oxidase enzyme, which reduces oxygen to superoxide anion in the respiratory burst. Neutropenia, infectious complications and impaired neutrophil function are often reported in glycogen storage disease type Ib (GSDIb), a metabolic disorder characterized by increased glycogen and decreased glucose-6-phosphatase (G-6-P) activity in the liver. Two children with GSDIb and associated neutropenia with recurrent bacterial infections were treated daily with different doses of rHu-GM-CSF. NADPH oxidase activity and chemotaxis in patients were assessed before and during therapy in stimulated and unstimulated neutrophils. During rHu-GM-CSF treatment, any increase found in the NADPH oxidase activity of patients was not significant with respect to that in controls. In one patient chemotaxis was greater than of controls. This finding suggests that in patients with GSDIb both neutropenia and PMN abnormalities may be responsible for infections, and PMN dysfunction probably depends on the degree of inherited functional G-6-P deficit.
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PMID:NADPH oxidase activity and chemotaxis by neutrophils in two patients with glycogen storage disease type Ib treated with recombinant human granulocyte-monocyte colony-stimulating factor. 864 44

Reperfusion injury, precipitated by lack of oxygen, is likely to play a major role in many clinical conditions, including shock, coronary artery occlusion disease, and solid organ transplantation. Certain tissues, such as the intestinal mucosa, may be especially susceptible because of the specific microvascular anatomy. Structural changes include not only swelling of the organelles but also the entire cell due to the entry of water and electrolytes. Lysosomal ruptures precede cell death. Other key substances which either participate in or are part of oxygen free radical formation in tissue injury are calcium ions, leukocytes, and bacteria. Leukocyte adhesion has been implicated as a critical step in vascular endothelium injury, leading to increased microvascular permeability and thrombosis. Induction of neutropenia or the administration of antileukocyte adhesion monoclonal antibodies, preventing typical injuries, implies a central role of the white blood cells in reperfusion injury. Specifically, oxygen free radical formation in the intestines may trigger or cause injury in other distant organs, e.g., the heart and lungs, and affect overall vascular function. So-called "bacterial translocation" from the intestines to the lymphatic vessels and the bloodstream is a more recently discovered phenomenon whose role is largely unknown. Ischemic preconditioning is still another concept, mainly tested in the canine heart, that has potential clinical applications. Reperfusion of ischemic tissue occurs with solid organ transplantation, often after considerable cold ischemia time. Protective mechanisms include oxygen free radical scavengers, i.e., allopurinol and superoxide dismutase. Other measures proven to be effective during the implantation are blood volume expansion with colloid solutions and/or electrolyte solutions, and the administration of a calcium antagonist. The mechanisms of these measures are likely related to improved renal microcirculation and relief of vasospasm.
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PMID:Reperfusion injury. 877 98

In vitro, endotoxin primes polymorphonuclear leukocytes (PMNs) to respond with a greater oxidative burst. The purpose of the present study was to investigate the in vivo effect of a wide range of single endotoxin bolus doses using a rat model. PMNs were subsequently challenged in vitro with phorbol ester to produce reactive oxygen intermediates (ROI). Flow cytometric determination of ROI production by large doses induced a decrease in ROI production by the few PMNs that remained in the circulation. By 6 h after injection, ROI production had returned to basal levels after a high dose, and was still increasing after a low dose. Neutropenia occurred immediately after endotoxin injection. After 6 h, PMN counts returned to almost normal levels with a high dose, but rebound neutrophilia occurred with a small dose. In contrast to in vitro studies, in vivo injection showed a response pattern that varied widely with dose and time of observation.
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PMID:Dose-response effect of in vivo administration of endotoxin on polymorphonuclear leukocytes oxidative burst. 915 92

Endotoxin-activated polymorphonuclear leukocytes (PMNL) adhere to the vascular endothelium and cause damage by the release of toxic superoxide anions (O2-). Because adenosine is a potent inhibitor of PMNL in vitro, the present study investigates the effects of this nucleoside on the functions of circulating PMNL in a standardized porcine model of hyperdynamic endotoxemia. Ten anesthesized pigs received an intravenous (i.v.) 330-min infusion of endotoxin (5 microg/kg of body weight per h). Another 10 pigs were also infused with endotoxin plus adenosine (150 microg/kg/min [i.v.]); this treatment was begun 30 min prior to the beginning of endotoxin treatment. Control groups (five animals per group) received either adenosine or physiological saline. Infusion of endotoxin caused severe neutropenia, shedding of L-selectin, upregulation of beta2-integrins, increased binding of C3-coated zymosan particles, and subsequent phagocytosis by PMNL. While phagocytosis-induced production of oxygen radicals appeared to decrease, extracellular release of superoxide anions was strongly enhanced. Infusion of adenosine during endotoxemia had no effect on neutropenia, expression of adhesion molecules, C3-induced adhesion, phagocytosis, or intracellular production of oxygen radicals, whereas extracellular release of O2- was strongly inhibited. Thus, i.v. infusion of adenosine during endotoxemia could be useful in protecting from O2(-)-mediated tissue injury without compromising the bactericidal mechanisms of PMNL.
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PMID:Effects of adenosine on the functions of circulating polymorphonuclear leukocytes during hyperdynamic endotoxemia. 916 43

The disturbances of polymorphonuclear neutrophil leucocytes (PMNLs) may be considered as a one of the causes of chronic or recurrent respiratory tract infections (RTI). The study carried out on patients with chronic or recurrent RTI was aimed at attempting to assess the dependence of clinical manifestations of RTI on nonspecific PMNLs dependent cellular response status. We used the chemiluminescence (CL) assay to study the ability of PMNLs to generate free oxygen forms during phagocytosis process. CL response of PMNLs to chemotactic peptide FMLP in 48 chronic and/or recurrent RTI patients and in 50 healthy blood donors of similar age (control group) was evaluated. RTI do not seem to be dependent on decreased PMNLs count (mild neutropenia was found in 35% of patients), but they may result from impaired function of PMNLs. All the values of CL response in RTI patients were lower than the lowest value observed in control group and ranged from 2.9 to 27.6 x 10(3) cpm/10(3) PMNLs. The lowest of PMNLs CL test value were found in patients with infections of pulmonary tissue (recurrent pneumoniae). The patients with infections of higher parts of respiratory tract (nasal cavity, sinuses, pharynx, trachea and bronchi) did not present such levels of PMNLs function impairment.
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PMID:[Disturbances of polymorphonuclear neutrophil leukocyte chemiluminescence in patients with chronic or recurrent respiratory tract infections]. 948 39

Inhaled platelet-activating factor (PAF), both in normals and in asthmatic patients, provokes transient systemic effects, neutropenia, bronchoconstriction and arterial oxygenation abnormalities similar to those shown in spontaneous exacerbations of asthma. To investigate the efficacy of a new PAF-receptor antagonist, SR 27417A, on all these changes after PAF challenge, 12 nonsmoking patients (four females and eight males) (mean+/-SEM) age 24+/-1 yrs with mild asthma (forced expiratory volume in one second (FEV1) 93+/-3% predicted) were studied in a double-blind, placebo-controlled, cross-over fashion 2 weeks apart. PAF aerosol challenge (18 microg) was carried out 3 h after oral administration of either SR 27417A (20 mg) or placebo. Respiratory system resistance (Rrs) and arterial blood gases and neutrophil cell counts were measured at baseline, before compound/placebo administration, and at 5, 15 and 45 min after PAF. Compared to vehicle, SR 27417A brought about moderate attenuation of PAF-induced neutropenia at 5 min (by 140%; p<0.025), and rebound neutrophilia at 15 and 45 min (p<0.025), increases of Rrs (by 90-65%) (p<0.01) and of alveolar-arterial pressure difference for oxygen (PA-a,O2) at 5 min (by 68%) and 15 min (by 63%), and decreases of arterial oxygen tension (Pa,O2) at 5 min (by 57%; p<0.025, each). Furthermore, systemic effects and platelet aggregation tests (p<0.001) were abolished after the administration of the compound. We conclude that SR 27417A is effective in inhibiting systemic, cellular and pulmonary effects after platelet-activating factor challenge in patients with mild bronchial asthma.
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PMID:Effect of a platelet-activating factor (PAF) antagonist, SR 27417A, on PAF-induced gas exchange abnormalities in mild asthma. 962 85

The purpose of the study was to examine the effects of buflomedil hydrochloride (BFL) on the expression of adhesion molecules (beta2-integrins) and oxygen radical production of circulating and emigrated intra-abdominal polymorphonuclear leukocytes (PMNL) in a standardized porcine model of hyperdynamic endotoxemia. A total of 20 anesthetized pigs were randomly assigned to one of the following groups: endotoxin group (endotoxin 5 microg / kg x h, intravenously (i.v.), n = 7), BFL group (BFL (3 mg/kg initial i.v. bolus followed by a continuous infusion (.1 mg / kg x h) and endotoxin 5 microg / kg x h, i.v., n = 7), and control group (NaCl .9%; n = 6). Experiments were terminated at 330 min. Infusion of endotoxin alone resulted in the activation of circulating and emigrated PMNL as evidenced by neutropenia, functional and numerical up-regulation of beta2-integrins, and enhanced oxygen radical production. BFL was able to attenuate functional and numerical up-regulation of beta2-integrins as well as oxygen radical production of circulating and emigrated PMNL. An unexpected decrease in the plasma concentration of BFL during the experiments was associated with an increase in the oxygen radical production of PMNL at the end of the experiments. In addition, BFL attenuated the fall in the intramucosal pH and the increase in plasma concentration of lactate observed in the late phase of endotoxemia. These findings suggest that BFL is able to decrease systemic activation of PMNL and to improve local tissue oxygenation during endotoxemia.
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PMID:Buflomedil hydrochloride reduces systemic activation of polymorphonuclear leukocytes during hyperdynamic endotoxemia. 984 Jun 48

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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