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)

Acid aspiration leads to increased neutrophil (PMN) oxidative metabolism, an event associated with lung leukosequestration and permeability increase. Neutropenia protected the vascular barrier function against acid injury. This study tests whether active oxygen species and elastase (which are presumably released by adherent PMNs) affect the microvascular barrier. Anesthetized rats underwent tracheostomy and insertion of a cannula into a lung segment. This was followed by localized instillation of 0.1 N HCl (n = 18) or saline (n = 18). Sequestration of PMNs in acid-aspirated and nonaspirated segments was 77 and 46 PMNs/high-power field (HPF), respectively, which was higher than control values of 11 and 8 PMNs/10 HPF in saline-aspirated and nonaspirated regions (P less than 0.05). Acid aspiration was associated with increased protein concentration in bronchoalveolar lavage (BAL) fluid to 3,550 and 2,900 micrograms/ml in the aspirated and nonaspirated lungs, respectively, which were higher than control values of 420 and 400 micrograms/ml (P less than 0.05). Acid aspiration also led to increased lung wet-to-dry weight ratios (W/D) of 6.6 and 5.4, which were higher than control values of 3.4 and 3.3 (P less than 0.05). Intravenous treatment of rats (n = 18) 90 min after aspiration with scavengers of reactive oxygen species, superoxide dismutase (1,500 U/kg), and catalase (5,000 U/kg), both conjugated to polyethylene glycol, did not reduce PMN sequestration but attenuated acid aspiration-induced increase in protein accumulation in BAL fluid in the aspirated and nonaspirated segments (990 and 610 micrograms/ml) as well as the increased lung W/D (4.6 and 4.0; all P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reactive oxygen species and elastase mediate lung permeability after acid aspiration. 139 82

To determine the mechanisms whereby complement-activated granulocytes induce microvascular dysfunction in skeletal muscle, we examined the effect of antineutrophil serum (ANS), IB4 (a monoclonal antibody that inhibits CD18-dependent neutrophil adherence), xanthine oxidase inhibition or inactivation, deferoxamine, and catalase on the increase in canine gracilis muscle microvascular permeability induced by intravascular administration of zymosan-activated plasma (ZAP). Changes in vascular permeability were assessed by measurement of the solvent drag reflection coefficient (sigma) for total plasma proteins, and the extent of neutrophil infiltration was estimated by assessing muscle myeloperoxidase activity. ZAP infusion was associated with a marked increase in vascular permeability compared with control muscles that received no treatment or to muscles treated with zymosan heat-inactivated plasma (ZIP) (sigma = 0.51 +/- 0.04, 0.89 +/- 0.02, and 0.90 +/- 0.01, respectively). Estimates of sigma in animals rendered neutropenic with ANS, or treated with IB4, deferoxamine, or catalase before ZAP infusion were not significantly different from values obtained in control or ZIP-treated muscles (sigma = 0.96 +/- 0.02, 0.88 +/- 0.03, 0.85 +/- 0.02, and 0.79 +/- 0.01, respectively). However, xanthine oxidase inactivation or inhibition provided no protection from this ZAP-induced microvascular dysfunction (sigma = 0.58 +/- 0.02 and 0.58 +/- 0.01, respectively). In addition, neutropenia and inhibition of neutrophil adherence also prevented ZAP-induced increases in vascular resistance and tissue neutrophil infiltration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxidant-mediated, CD18-dependent microvascular dysfunction induced by complement-activated granulocytes. 167 94

1. Oleic acid was used to produce adult respiratory distress syndrome-like pulmonary microvascular injuries. The resulting injuries have previously indicated involvement of accumulating neutrophils (Hultkvist et al. 1988). Activated neutrophils release oxygen free radicals that may be possible to detect in the plasma. 2. The dynamics of neutrophils and platelets were studied in the guinea-pig after oleic acid-induced injury (0.03 ml/kg per 10 min). 3. As an indication of oxygen free radical activity, plasma levels of uric acid and red blood cell (RBC)-catalase, were analysed. 4. Allopurinol (10 mg/kg, i.p.) was given prior to oleic acid infusion to block the production of uric acid. 5. The neutropenia, in contrast to the thrombocytopenia seen at 15 min, was significantly inhibited in the allopurinol pretreated group compared with oleic acid and vehicle alone. 6. The blood plasma concentration of uric acid was significantly elevated after 15 min from start of experiment. Allopurinol pretreatment significantly reduced the uric acid plasma level. 7. The RBC catalase activity did not change with time within or between any groups. 8. The results indicate that sequestration of activated neutrophils in the microvasculature are to some extent oxygen free radical dependent.
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PMID:Oleic acid-induced injuries in the guinea-pig. Effects of allopurinol on cell dynamics, erythrocyte-catalase and uric acid plasma levels. 205 54

Nine anesthetized pigs were subjected to short (90 min) sham dialysis with blood membrane contact with the aim to select effects of the artificial surface during dialysis. The importance of the neutrophil (PMN) was investigated by the selective isotope labelling, dynamically followed by gamma-camera imaging and biochemical assays specifically oriented for PMN function. These assays included cell count, PMN aggregation, PMN luminescence, fibronectin and catalase activity. Additionally, pulmonary and systemic hemodynamics and acid base balance were monitored. Sham dialysis induced an accumulation of labelled PMN attaining a maximum between 15 and 17 min. This was coupled with a time-related neutropenia, pulmonary vasoconstriction, increased in vitro PMN aggregation and luminescence response. The neutrophil response abated by the end of dialysis. Cardiac output and arterial blood pressure declined to a steady level after 30 min of sham dialysis. There was an insignificant decrease in catalase activity. All other parameters remained unaltered. The results indicate that PMN accumulates in the pulmonary vessels, in association with neutropenia and activation. The transience of the event points to a protective mechanisms of humoral and/or cellular character.
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PMID:Dynamic pulmonary accumulation of labelled neutrophils by blood membrane contact in the pig. 223 54

Ethanol-induced gastric mucosal injury closely resembles an inflammatory response. Thus, in vivo and in vitro experimental models were used to assess whether ethanol is proinflammatory in concentrations likely to be encountered by the gastric mucosa during acute intoxication. Perfusing the rat gastric lumen with progressively increasing concentrations of ethanol (10%, 20%, and 30%) resulted in a dose-dependent increase in 51Cr-ethylenediaminetetraacetic acid clearance from blood-to-gastric lumen. Rendering the animals neutropenic (with antineutrophil serum) ameliorated the ethanol-induced mucosal injury; the degree of protection was directly related to the severity of neutropenia. Neither superoxide dismutase, catalase, nor sodium benzoate offered any protection against ethanol-induced injury, indicating that neither superoxide anion, hydrogen peroxide, nor the hydroxyl radical is involved. To assess further whether ethanol could exert proinflammatory effects an in vitro model consisting of cultured bovine microvascular endothelial cells and isolated human neutrophils was used. Ethanol at concentrations of 1.0%-4.0% (but not at 0.1%-0.5%) increased neutrophil adherence to endothelial cells and enhanced neutrophil-mediated endothelial cell injury. We conclude that ethanol is proinflammatory at concentrations that may be achieved in the gastric mucosa during acute intoxication. The ethanol-induced, neutrophil-mediated cell injury does not appear to involve oxy radicals.
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PMID:Ethanol-induced injury to the rat gastric mucosa. Role of neutrophils and xanthine oxidase-derived radicals. 231 75

Vascular pathways are major transit routes for the dissemination of malignant neoplasms and are also regulators of cancer metastasis, in part because the endothelium and vascular basement membrane are barriers to the entry and exit of tumor cells. In this study, we have examined the hypothesis that host cell-mediated damage to the pulmonary microvasculature facilitates the experimental metastasis of a syngeneic fibrosarcoma in the C57BL/6J mouse. Intravenous injection of purified cobra venom factor was followed in 30 minutes by complement activation, neutropenia with sequestration of neutrophils in the lung, and increased pulmonary vasopermeability. When syngeneic fibrosarcoma cells were injected simultaneously with cobra venom factor, there was a 3 fold increase in cancer cell retention in the lungs after 24 hours and a 3- to 20-fold increase in metastatic tumor burden after 14 days. Enhanced cancer cell retention after cobra venom factor was not seen in mice deficient in complement component C5 and was diminished by pretreatment of animals with antineutrophil antibodies, catalase, inhibitors of lipoxygenase, thromboxane synthetase, and lipid peroxidation (oxygen radical scavenger). We conclude that neutrophil-mediated microvascular injury can promote the organ localization and metastasis of circulating cancer cells.
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PMID:Effects of systemic complement activation and neutrophil-mediated pulmonary injury on the retention and metastasis of circulating cancer cells in mouse lungs. 231 52

Neutrophilic leukocytes have been implicated as important mediators of ischemic myocardial injury. We investigated the role of neutrophils in skeletal muscle ischemia/reperfusion injury by using the rat hindlimb ischemia model. We rendered Wistar rats neutropenic by administering 750 rad of whole-body radiation (mean white blood cell count, 300 +/- 50/mm3; 3 days after radiation). In anesthetized rats (10 neutropenic and 10 control), 3 hours of ischemia were induced in one hindlimb by application of a tourniquet to the proximal thigh; the contralateral limb served as an internal, nonischemic control. After 1 hour of reperfusion the gastrocnemius and soleus muscles were excised bilaterally and evaluated for ischemic injury by means of a quantitative spectrophotometric assay of triphenyltetrazolium chloride (TTC) reduction. In control rats the reduction of TTC by ischemic muscle averaged 27.0% +/- 7.3% of that by nonischemic muscle; whereas in neutropenic rats the value for ischemic muscle was 65.4 +/- 11.6% (p less than 0.05). To determine if the contribution of the neutrophils to ischemic injury is due to oxygen-derived free radical formation, an additional 10 animals were infused with 5000 units of super-oxide dismutase and 10,000 units of catalase at the time reperfusion was restored. After treatment with free radical scavengers, TTC reduction by ischemic limbs was 25.5% +/- 7.0% of that by nonischemic limbs and did not differ from that in control animals (p greater than 0.05). The results show a protective effect of neutropenia and suggest a significant role of the white cell in the pathophysiology of ischemic skeletal muscle injury.
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PMID:The role of leukocytes in the pathophysiology of skeletal muscle ischemic injury. 247 24

The mechanisms underlying drug-induced neutropenia are poorly characterized. We have examined the mechanism of suppression of granulocytopoiesis by captopril and penicillamine using human and canine bone marrow cells in an in vitro culture system. Addition of captopril caused no significant change in granulocyte-macrophage colony formation at concentrations up to 30 micrograms/ml. In the presence of CuSO4 (1-3 micrograms/ml), however, captopril caused significant inhibition of colony growth (p less than 0.05). Penicillamine, another agent associated with neutropenia and, like captopril, having a reactive thiol group, also inhibited colony formation in the presence of copper. Chemical congeners of captopril lacking a reactive thiol group and enalaprilic acid, an alternative angiotensin-converting enzyme (ACE) inhibitor, failed to show inhibition, suggesting that the thiol group and not ACE inhibition was responsible. Analysis of day-7 colonies (98% neutrophilic) and day-21 colonies (37% neutrophilic, 30% macrophagic, 27% eosinophilic, and 6% mixed) showed that neutrophil-containing colonies, but not nonneutrophilic colonies were inhibited by the addition of captopril plus copper. Catalase totally reversed the inhibition of colony formation caused by these agents. Direct measurement of oxygen consumption in the presence of captopril showed marked enhancement with the addition of CuSO4 and a 48% reduction in the presence of added catalase. These data indicate that drugs with a reactive thiol group can interact with copper to generate H2O2, which can be toxic to neutrophilic progenitor cells. We postulate that this may be an important mechanism for drug-associated neutropenia and a general mechanism for drug-induced marrow cell injury.
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PMID:Suppression of in vitro granulocytopoiesis by captopril and penicillamine. 284 Nov 47

Reactive oxygen species have been proposed as pathophysiological factors responsible for the hypodynamic circulatory response to gram-negative endotoxin. To test this hypothesis, we examined the cardiorespiratory effects of mechanistically different oxygen free radical scavenging agents during Escherichia coli endotoxemia in beagle dogs. Pentobarbital-anesthetized dogs were instrumented for repeated sampling of cardiorespiratory, hematologic, and tissue blood flow (radiolabeled 15-micron microspheres) indexes. Four groups were studied: 1) time-matched control dogs (n = 6); 2) dogs receiving only endotoxin (1.5 mg/kg; n = 6); 3) dogs receiving endotoxin and combination therapy with allopurinol (150 mg/kg) plus superoxide dismutase (5 mg/kg) and catalase (5 mg/kg; n = 6); and 4) dogs receiving endotoxin and deferoxamine (30 mg/kg; n = 5). Measured variables in control dogs were constant during the 4-h study, whereas endotoxin-injected dogs consistently demonstrated the following: 1) maintained reductions in blood pressure (greater than 45%), left ventricular systolic pressure (greater than 43%), left ventricular maximum rate of pressure development (+/- dP/dtmax) (greater than 41%), cardiac index (greater than 33%), and blood flow in all sampled tissues except liver and skeletal muscle; 2) transient tachypnea, bradycardia, and arterial acidosis; and 3) persistent neutropenia and hemoconcentration. Neither of the free radical scavenging protocols significantly improved measured variables during endotoxemia (P greater than 0.05). This lack of efficacy suggests that superoxide anion, hydrogen peroxide, and hydroxyl radical may lack primary pathophysiological importance during the development of E. coli endotoxicosis in intact dogs.
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PMID:Evidence for lack of importance of oxygen free radicals in Escherichia coli endotoxemia in dogs. 328 94

Neutrophils have been implicated in the pathogenesis of acute lung injury associated with clinical and experimental sepsis. Data from in vitro systems and experimental animals have suggested that neutrophil-derived oxidants, particularly H2O2, may be primarily responsible for endothelial damage, vasoconstriction, and lung edema. With the use of endotoxin infusion as an in vivo model of sepsis we tested the hypothesis that pretreatment with catalase, a peroxide scavenger, would ameliorate the resultant changes in pulmonary vasoconstriction and lung fluid balance. Paired experiments were performed in 16 goats with chronic lung lymph fistulas. One group of animals (n = 7) received endotoxin first alone and then again, several days later, after pretreatment with Ficoll-linked catalase. As a control, identical experiments were performed in a separate group (n = 6) with Ficoll-linked albumin substituted for Ficoll-catalase. A third group (n = 3) was given endotoxin alone and then again during a continuous infusion of catalase. Plasma and lymph levels of catalase were comparable to or exceeded those previously shown to be completely protective in isolated perfused lung preparations and in vitro systems. Endotoxin caused neutropenia, pulmonary arterial hypertension, decreased cardiac output, and increases in lymph flow to approximately three times base line, with a return of all variables toward control values by 6 h. Catalase pretreatment produced no significant differences in any of these variables. These experiments do not support a role for H2O2 as a mediator of acute lung injury due to endotoxemia.
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PMID:Effect of intravenous catalase on the pulmonary vascular response to endotoxemia in goats. 328 99


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