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 have previously shown that intravascular platelet activating factor (PAF) causes ischemic bowel necrosis in rats morphologically similar to neonatal necrotizing enterocolitis (NEC). Because endotoxin (LPS) and hypoxia are risk factors for NEC, we studied their effect on PAF metabolism and the development of intestinal injury. Young male Sprague-Dawley rats were anesthetized with pentobarbital and divided into six experimental groups: 1) control, 2) LPS alone (2 mg/kg), 3) hypoxia alone (5% O2), 4) LPS+hypoxia, 5) WEB 2086 (PAF antagonist)+LPS+hypoxia, and 6) SRI 63-441 (PAF antagonist)+LPS+hypoxia. Evaluations included blood pressure recording, superior mesenteric artery blood flow, arterial blood gas, white blood cell count, hematocrit, plasma PAF, plasma acetylhydrolase, plasma tumor necrosis factor, intestinal perfusion, and intestinal injury at 3 h. We found that LPS+hypoxia synergistically contributed to hypotension (mean blood pressure 27 +/- 5.6% baseline versus 101 +/- 3.9% control), metabolic acidosis (pH 7.05, base deficit 24 mEq/L), hemoconcentration, decreased superior mesenteric artery blood flow (2.2 +/- 0.3 mL/min versus 5.8 +/- 0.2 mL/min control), and intestinal injury. The morbidities resulting from LPS+hypoxia were partially or completely prevented by PAF antagonists. In addition, animals treated with LPS+hypoxia had neutropenia, elevated plasma acetylhydrolase, and elevated plasma TNF. These results suggest that endogenous PAF may contribute to LPS+hypoxia-induced intestinal hypoperfusion and necrosis.
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PMID:Endotoxin and hypoxia-induced intestinal necrosis in rats: the role of platelet activating factor. 160 19

We assessed the role of platelet-activating factor (PAF) in mediating the pulmonary hemodynamic and lymph flow responses to tumor necrosis factor-alpha (TNF alpha). The effects of the PAF receptor antagonist WEB 2086 on TNF alpha-induced pulmonary vasoconstriction and increased pulmonary transvascular plasma-lymph protein transport were examined. Control (n = 7) and WEB-2086-pretreated (n = 7) sheep prepared with chronic lung lymph fistulas were challenged with recombinant human TNF alpha (12 micrograms/kg over 0.5 h). Ex vivo challenge of platelet-rich plasma (PRP) with 10(-8) M PAF resulted in aggregation of platelets from control TNF-challenged sheep, but not of platelets from WEB-treated sheep similarly challenged with TNF. The control TNF-alpha-challenged sheep developed hemoconcentration, leukopenia, and neutropenia. TNF alpha resulted in increases in pulmonary arterial pressure (Ppa) and pulmonary vascular resistance (PVR) within 15 min, and the values were sustained for the 5-h experiment duration. Pulmonary lymph flow (Qlym) and pulmonary transvascular protein clearance rate (Qlym x lymph-to-plasma protein concentration) were increased within 30 min and remained elevated for 5 h. The WEB-2086-treated sheep developed similar leukopenia and neutropenia after TNF alpha challenge, but the initial increases in Ppa and PVR were significantly reduced (p less than 0.05). However, WEB 2086 did not prevent the threefold increases in Qlym and transvascular protein clearance induced with TNF alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of platelet-activating factor in mediating tumor necrosis factor alpha-induced pulmonary vasoconstriction and plasma-lymph protein transport. 174 48

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

The diversity of infectious agents capable of inducing meningitis and blood-brain barrier (BBB) injury suggests the potential for a common host mediator. The inflammatory polypeptides, IL-1 and TNF, were tested in an experimental rat model as candidate mediators for induction of meningitis and BBB injury. Intracisternal challenge of rIL-1 beta into rats induced neutrophil emigration into cerebrospinal fluid (CSF) and significantly increased BBB permeability to systemically administered 125I-BSA as early as 3 h later (P less than 0.05). This injury was reversible, dose dependent and significantly inhibited by prior induction of systemic neutropenia (via intraperitoneal cyclophosphamide) or preincubation of the rIL-1 beta inoculum (50 U) with an IgG monoclonal antibody to rIL-1 beta. Similar kinetics and reversibility of CSF inflammation and BSA permeability were observed using equivalent dose inocula of rIL-1 alpha. rTNF-alpha was less effective as an independent inducer of meningitis or BBB injury over an inoculum range of 10(1) U (0.0016 micrograms/kg)-10(6) U (160 micrograms/kg) when injected intracisternally, but inoculum combinations of low concentrations of rTNF alpha (10(3) U) and rIL-1 beta (0.0005-5.0 U) were synergistic in inducing both meningitis and BBB permeability to systemic 125I-BSA. These data suggest that in situ generation of interleukin-1 within CSF (with or without TNF) is capable of mediating both meningeal inflammation and BBB injury seen in various central nervous system infections.
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PMID:Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat. Characterization and comparison with tumor necrosis factor. 201 May 49

The macrophage- and monocyte-produced cytokine tumor necrosis factor alpha (TNF alpha) has been proposed as a major mediator of endotoxin-induced injury. To determine if TNF alpha could reproduce the effects of endotoxin on the lung, we intravenously administered 10 micrograms/kg of human recombinant TNF alpha into five chronically instrumented unanesthetized sheep on two occasions to characterize the TNF alpha response and its reproducibility. We assessed changes in lung mechanics, pulmonary and systemic hemodynamics, gas exchange, and the number and type of peripheral blood leukocytes. We also determined airway reactivity by use of aerosolized histamine before and after TNF alpha infusion. Pulmonary arterial pressure (Ppa) peaked within 30 min of initiating the TNF alpha infusion [47.7 +/- 2.2 vs. 15.9 +/- 0.4 (SE) cmH2O at base line] and then returned toward base line over 4 h. There was a brief decline in left atrial pressure after TNF alpha. Pulmonary hypertension was accompanied by leukopenia, neutropenia, and increases in the alveolar-arterial O2 difference (AaDO2). Dynamic lung compliance (Cdyn) declined after TNF alpha, reaching a nadir within 15 min of the initiation of the TNF alpha infusion [0.045 +/- 0.007 vs. 0.093 +/- 0.007 (+/- SE) l/cmH2O at base line]. Resistance to airflow across the lung (RL) increased from 1.2 +/- 0.2 cmH2O.l-1.s at base line, peaking at 5.4 +/- 1.3 cmH2O.l-1.s 30 min after the start of the TNF alpha infusion. Alterations in Cdyn and RL persisted for 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor necrosis factor's effects on lung mechanics, gas exchange, and airway reactivity in sheep. 238 33

In in vitro experiments, tumor necrosis factor (rHuTNF alpha) was found to inhibit spontaneous and directed migration of normal human neutrophils and monocytes. RHuTNF alpha showed no chemoattractant activity. In conjunction with a Phase-2 clinical trial, we also studied in vivo rHuTNF alpha effects on neutrophil and monocyte number and function. At the time of maximal plasma TNF levels (30 min), marked neutropenia and monocytopenia were observed. Isolated neutrophils were activated for superoxide production but were unable to migrate. Monocyte migration was inhibited at later times. Neutrophil migratory function recovered between 4 and 8 h but was again depressed at 24 h. The data demonstrate the complexity of the response to TNF, comprising direct and indirect effects which are concentration-, time- and place-dependent. They further suggest that the only neutrophils and monocytes available for participation in an anti-tumor activity of TNF in vivo are those present in the tumor at the outset.
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PMID:Effects of recombinant tumor necrosis factor (rHuTNF alpha) on human neutrophils and monocytes: in vitro, ex vivo and in vivo. 255 13

Recombinant human IL-3 administered intravenously to rats as a single injection induced peripheral neutrophilia and monocytosis beginning at 4 to 6 hours after injection, peaking at 8 hours, and subsiding to normal by 12 to 24 hours. IL-3 did not induce an initial neutropenia such as accompanies endotoxin-, G-CSF-, and TNF-induced neutrophilia, or lymphopenia such as accompanies endotoxin-, IL-1-, and TNF-induced neutrophilia. The IL-3-induced peripheral neutrophilia was accompanied by a decrease in mature marrow neutrophils, indicating that the mechanism of neutrophilia was through marrow release rather than by demargination, which occurs after the administration of epinephrine or IL-6. The release of mature marrow neutrophils further suggests that IL-3 either has intrinsic neutrophil releasing activity or indirectly causes neutrophil release through the gene expression of a second cytokine. IL-3 induced a striking left-shifted myeloid hyperplasia in the bone marrow at 8 hours that morphologically was very similar to that observed after administration of endotoxin, a finding consistent with the hypothesis of previous investigators that endotoxin may in part act indirectly on hematopoietic cells by eliciting local marrow production of IL-3. Finally, IL-3 induced an increase in marrow pronormoblasts at 8 hours, consistent with the in vitro proliferative effect of IL-3 on erythroid stem cells. The combination of IL-3 and IL-6 induced a synergistic peripheral neutrophilia and monocytosis and a striking synergistic increase in marrow mast cells. The combination of IL-3 and IL-6 also induced an erythroid and left-shifted myeloid hyperplasia such as would be expected given the individual effects of these hematopoietic growth factors.
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PMID:Acute in vivo effects of IL-3 alone and in combination with IL-6 on the blood cells of the circulation and bone marrow. 280 84

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

Human recombinant interleukins 1 alpha and 1 beta (rIL-1 alpha and -1 beta) both induced monophasic peripheral neutrophilia and lymphopenia in Lewis rats 1.5 hr after i.v. injection. The kinetics of rIL-1 alpha- and -1 beta-induced neutrophilia were similar to those induced by human monocyte-derived IL-1, IL-1 alpha, and IL-1 beta, and the peripheral neutrophilia was accompanied by a marked decrease in marrow neutrophils. Arachidonic acid metabolites are implicated as biochemical intermediates in the production of the neutrophilia but not lymphopenia, since indomethacin and dexamethasone both completely abrogated IL-1-induced neutrophilia but did not affect the IL-1-induced lymphopenia. Acetylsalicylic acid, a cyclooxygenase inhibitor, did not inhibit IL-1-induced neutrophilia, suggesting that products of the lipoxygenase rather than the cyclooxygenase pathway of arachidonate metabolism may contribute to the neutrophilia. Human recombinant tumor necrosis factor-alpha (rTNF) administered i.v. to Lewis rats induced peripheral neutropenia, two peaks of neutrophilia, and lymphopenia. A wide range of doses of rTNF resulted in an initial neutropenia at 0.5 hr after injection followed by a first peak of neutrophilia at 1.5 hr and a second peak of neutrophilia at 6 hr. The initial neutropenia and the first peak of neutrophilia were not inhibited by pretreatment of rats with dexamethasone, indomethacin, or aspirin. The second peak of neutrophilia was inhibited by both dexamethasone and indomethacin, but was not at all inhibited by aspirin, suggesting that the second peak of neutrophilia is mediated by the release of endogenous cytokines, especially by IL-1, since exogenous IL-1-induced neutrophilia is also completely inhibited by dexamethasone and indomethacin but not by aspirin. The TNF-induced peripheral neutrophilia is also accompanied by a significant depletion of bone marrow neutrophils, indicating that the source of increased circulating neutrophils is, at least in part, via recruitment of marrow neutrophils. Systemic blood pressure was not affected by IL-1 or rTNF at the dosages employed, showing that the changes in circulating leukocyte subsets were not attributable to hemodynamic changes nor to the hemodynamic change-related release of adrenal hormones. Adrenalectomy did not alter the IL-1- or rTNF-induced neutrophilia or lymphopenia, also demonstrating that neither monokine mediates its hematologic effects on peripheral blood leukocytes via the release of adrenal hormones.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Kinetics and mechanisms of recombinant human interleukin 1 and tumor necrosis factor-alpha-induced changes in circulating numbers of neutrophils and lymphocytes. 331 83

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


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