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 present study demonstrates that CSA is capable of inhibiting indomethacin-induced leukocyte adherence to the vascular endothelium, and can reduce the severity of indomethacin-induced gastric mucosal injury. These results are therefore consistent with the hypothesis that leukocyte (particularly neutrophil) adherence is a critical event in the pathogenesis of NSAID-induced gastropathy. The mechanism through which CSA inhibits leukocyte adherence is not clear, and warrants further investigation. This study also confirmed the protective effects of IL-1 in experimental NSAID-gastropathy, and demonstrates that one of the ways the IL-1 may protect the mucosa is through its ability to inhibit the release of proinflammatory mediators (e.g., PAF) and promote the release of antiinflammatory mediators (e.g., nitric oxide). IL-1 modulated the release of these mediators from peritoneal mast cells at doses in the pg/ml to ng/ml range. IL-1 can inhibit the ability of neutrophils to respond to chemotactic stimuli and can prevent LTB4-induced neutropenia. Inhibition of neutrophil function by IL-1 may therefore account for its ability to reduce NSAID-induced gastric mucosal injury. Whether or not effects of IL-1 on the production of mediators such as nitric oxide and PAF is an underlying mechanism for the inhibitory effects on neutrophil function remains to be determined.
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PMID:Immunopathology of NSAID-gastropathy: inhibitory effects of interleukin-I and cyclosporin A. 145 66

Endotoxin is a potent inflammatory stimulus and induces polymorphonuclear leukocyte (PMNL) infiltration into tissues. Macrophage (M phi) derived IL-1 has been proposed as a mediator of this response. TNF alpha is also produced by M phi s in response to endotoxin and both IL-1 and TNF enhance PMNL adhesion to vascular endothelium in vitro. We investigated the activity of recombinant human IL-1 alpha, IL-1 beta, and TNF alpha in inducing PMNL infiltration into the skin of rabbits using a quantitative 51Cr labelled blood leukocyte assay. IL-1 alpha and IL-1 beta induced progressive PMNL accumulation, the 50% maximal response being induced by approximately equal to 20 units. In comparison, TNF alpha even at 100,000 U, induced only mild PMNL accumulations, although IL-1 alpha and TNF alpha were similarly active in inducing PMNL adherence to human umbilical vein endothelium. The human TNF alpha preparation was pyrogenic and induced acute, transient neutropenia in rabbits upon i.v. infusion, IL-1 alpha, IL-1 beta and TNF alpha are often secreted simultaneously by M phi s, therefore we investigated their action in combination. The combination of IL-1 alpha with IL-1 beta was nearly additive in inducing PMNL accumulation, i.e., 87% of predicted result based on the sum of the responses to individual components. The combination of TNF alpha with either IL-1, each in submaximal doses, resulted in 65-125% greater than the additive response. No such effect was observed when these monokines were injected in combination with PMNL chemotactic stimuli. These results indicate a complex interaction between inflammatory monokines in the regulation of PMNL accumulation in vivo.
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PMID:Synergy between tumour necrosis factor alpha and interleukin-1 in the induction of polymorphonuclear leukocyte migration during inflammation. 325 46

The pathogenesis of acute lung injury in humans is obscure, but lipopolysaccharide (LPS), complement activation, and neutrophils have been implicated. We investigated in rabbits the interaction of small amounts of intravascularly administered LPS (100 ng) with neutrophil chemotactic factors, the synthetic chemotactic peptide formyl-norleucyl-leucyl-phenylalanine (FNLP), and the biologically relevant chemotactic fragments of C5 (C5f). These neutrophil stimuli produce neutropenia when injected intravascularly in rabbits, reflecting neutrophil adherence to vascular endothelium. When LPS was injected with FNLP, the duration of neutropenia was enhanced. Studies with radiolabeled neutrophils infused in vivo demonstrated prolonged neutrophil sequestration within the lung in rabbits that were given FNLP plus LPS, an effect that was visible for 4 h after injection. Morphometric analysis of tissue sections 4 h after infusion confirmed the presence of greater numbers of neutrophils in the lungs of animals receiving LPS and FNLP. When a combination of LPS and chemotactic factors was infused at both zero and 6 h, we found a marked enhancement of lung vascular permeability at 24 h (as assessed by radiolabeled albumin accumulation), an effect not seen with either LPS or chemotactic factor alone. Ultrastructural studies revealed neutrophil sequestration and alteration in endothelial cells in the animals that received the combination of LPS and chemotactic factors. Neutrophil depletion with nitrogen mustard completely abolished the increased vascular permeability seen in animals that received LPS and chemotactic factors. This study suggests that small amounts of intravascularly administered LPS enhance the sequestration of neutrophils within the lung and increase lung vascular permeability and endothelial injury caused by neutrophils stimulated by intravascularly administered chemotactic factors. This mechanism may be relevant to the production of acute lung injury in human beings.
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PMID:Neutrophil-mediated pulmonary vascular injury. Synergistic effect of trace amounts of lipopolysaccharide and neutrophil stimuli on vascular permeability and neutrophil sequestration in the lung. 330 Apr 42

Leukotriene B4 (LTB4 isomer III), which promotes the movement and aggregation of leucocytes in vitro also stimulates the chemo-attraction of leucocytes and their adherence to vascular endothelium in vivo. These effects were observed directly in the hamster cheek pouch preparation and on histological examination of sections from the rabbit mesentery. Intravenous injection of LTB4 (isomer III) into the rabbit resulted in a profound but transient neutropenia. Intradermal injection of LTB4 (isomer III) in the rabbit produced a rapid accumulation of neutrophils and this effect was also observed in skin chambers applied over abrasions on the rabbit back or the human forearm.
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PMID:Leukotriene B4: an inflammatory mediator in vivo. 627 Jul 42

L-selectin requirements in three models of acute lung injury in rats have been identified: systemic activation of complement after intravenous infusion of cobra venom factor (CVF) and intrapulmonary deposition of IgG or IgA immune complexes. In the CVF model of lung injury, treatment of rats with hamster monoclonal IgG anti-rat-L-selectin (HRL-1) induced significant neutropenia, necessitating the use of F(ab')2 fragments, which did not cause neutropenia. Treatment of rats with F(ab')2 anti-L-selectin (HRL-1) resulted in significant reductions in lung permeability and hemorrhage in the CVF model. Morphologically, this treatment abrogated adhesive interactions of neutrophils with the pulmonary vascular endothelium. In the IgG immune complex model of injury, the parameters of injury were significantly reduced as a result of treatment with HRL-1. In both models protection was associated with reductions in lung myeloperoxidase content. Treatment of rats with a F(ab')2 form of hamster monoclonal IgG non-blocking anti-L-rat selectin, HRL-2, failed to show protective effects in the CVF and IgG immune complex models of lung injury. In the IgA immune complex model of injury, which is neutrophil-independent and related to toxic products from pulmonary macrophages, no protective effects of anti-L-selectin (HRL-1) were found. Therefore, in neutrophil-dependent and oxygen radical mediated lung injury, L-selectin plays a requisite role in tissue recruitment of neutrophils. In the neutrophil-independent model of lung injury, no requirement for L-selectin appears to exist.
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PMID:Requirements for L-selectin in neutrophil-mediated lung injury in rats. 750 37

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

A murine anti-rat intercellular adhesion molecule 1 (ICAM-1) monoclonal antibody (mAb), 1A29, was used to investigate the importance of blood leukocyte-associated beta 2-integrin (CD11/CD18) vascular endothelium-associated ICAM-1 adhesive interactions in the reversed passive Arthus reaction (RPAR) in rats. An Arthus pleurisy reaction (4 h) was employed in these studies because it permits the accurate quantitation of polymorphonuclear neutrophil (PMN) influx into the pleural space and fluid accumulation. 1A29, which localized within Arthus lung lesions, caused a dose-dependent (0.5-2.0 mg/kg, i.v.) inhibition of PMN influx (19-56%) and exudate volume (9-55%) in the Arthus pleurisy reaction. P7 (2 mg/kg, i.v.), a murine anti-human P-selectin mAb used as an isotype-matched control for 1A29, did not localize at the lung lesion site and was inactive. Immunohistochemical analysis of lung tissue from 1A29-treated rats demonstrated increased granulocyte accumulation in the alveolar capillaries compared with more extensive granulocyte emigration into the lung tissue and pleural space in P7-treated rats and Arthus control rats; however, quantitative image analysis revealed increased numbers of lung granulocytes in 1A29-treated rats compared with controls. Neither ICAM-1 mRNA nor expression, assessed by immunocytochemistry, was increased above control levels in rats during the pleural Arthus reaction. Neutropenia was not observed in either 1A29- or P7-treated rats.
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PMID:ICAM-1 mediates leukocyte-endothelium adhesive interactions in the reversed passive Arthus reaction. 860 10

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

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

Glycosphingolipids (GSLs) are complex macromolecules on cell membranes that have been shown to play a role in neutrophil differentiation, activation, phagocytosis, and adhesion to both microorganisms and vascular endothelium. Because GSLs are often cryptic antigens on cell membranes, little is known regarding GSL expression in early myelopoiesis. To study the latter, myeloblasts were collected from patients with acute nonlymphocytic leukemia (ANLL) who required therapeutic leukocytopheresis for hyperleukocytosis. The neutral GSLs were isolated and identified by high-performance thin-layer chromatography (HPTLC), HPTLC immunostaining, gas chromatography, nuclear magnetic resonance, and fast atom bombardment-mass spectrometry. Like mature peripheral blood neutrophils, myeloblasts expressed glucosylceramide, lactosylceramide, and the neolacto-family GSLs, lactotriaosylceramide and neolactotetraosylceramide. Unlike neutrophils and chronic myeloid leukemia, most ANLL samples also expressed the globo-series GSLs, globotriaosylceramide and globotetraosylceramide. Globo GSL expression was strongly associated with a myeloblastic (ANLL M0-M2) and monoblastic phenotype (M5). A weak association was also noted with expression of either lymphoid (P <.10) or early hematopoietic markers (terminal deoxynucleotidyl transferase [TdT], CD34; P <.10). Globo-positive ANLL samples bound both shiga toxin and parvovirus B19 on HPTLC immunostaining. Based on these findings, we propose that neolacto and globo GSLs are expressed during early myeloid differentiation. Globotriaosylceramide expression on myeloblasts, and possibly myeloid stem cells, may have important implications for the use of shiga toxin as an ex vivo purging agent in autologous stem cell transplantation. Expression of globotetraosylceramide, the parvovirus B19 receptor, on myeloblasts may also explain the association between B19 infection, aplastic anemia, and chronic neutropenia of childhood.
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PMID:Glycosphingolipid expression in acute nonlymphocytic leukemia: common expression of shiga toxin and parvovirus B19 receptors on early myeloblasts. 1239 13


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