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)

It is thought that the nonsteroidal anti-inflammatory drugs act through inhibition of cyclooxygenase (CO). The authors show that the pyrazolon derivatives phenylbutazone (P) and sulfinpyrazone (S) affect PMN function in a manner independent of CO inhibition. During inflammation PMN often show increased adhesiveness. Such adhesiveness can be provoked in vitro by high concentrations of chemotaxins. Preincubation (10--20 minutes) of platelet-free human PMN suspensions in heat-inactivated plasma with 100 micrograms P or S per ml completely abolished a submaximal adherence induction on Petri dishes from 4% adherent cells in the absence, to 23% in the presence, of 10(-7) M of the chemotaxin N-f-Met-Leu-Phe (FP). In vivo, premedication of rabbits with P or S prevented the FP-induced neutropenia, e.g. 10 mg/kg of S blocked a 5-minutes agranulocytosis. P and S also abrogated adherence-induced lysosomal enzyme release and FP-stimulated hexose monophosphate pathway (HMP) activity. FP-induced hyperadhesiveness impedes PMN locomotion. Preincubation of PMN with P or S reestablished random motility and allowed chemotactic migration toward activated C (as C5a) in spite of the presence of 'adhesive' concentrations of FP. The potent CO inhibitors indomethacin and aspirin had no effect on FP-induced adherence, enzyme release, neutropenia and HMP stimulation. In 3 selected patients with PMN hyperadhesiveness, correction of this adhesiveness by P paralleled clinical remission. It is concluded that P and S exert their antiinflammatory action at least in part by interfering with PMN hyperadhesiveness and lysosomal enzyme release. These effects are independent of the prostaglandin-thromboxane system, since other CO inhibitors are uneffective.
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PMID:[Pharmacologic remobilization of hyperadhesive granulocytes: a new principle in "anti-inflammatory" therapy]. 48 16

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

GBS (Group B Hemolytic Streptococci) cause pulmonary hypertension with associated neutropenia. We investigated whether there is a correlation between the neutropenia of sepsis and GBS-induced pulmonary vasoconstriction, through study of the effects of inhibiting pulmonary vasoconstriction on the neutropenia of GBS in newborn piglets. Fifteen piglets were infused with GBS. After one hour, animals were given either a thromboxane inhibitor (DAZ), a combined cyclooxygenase/lipoxygenase inhibitor, BW755C, or placebo. With GBS infusion, WBC and PMN counts dropped steadily, from similar baselines, to 2250 +/- 570, 3300 +/- 500 and 5400 +/- 1100 cells/mm3 respectively (p less than 0.05; DAZ and BW vs. placebo). PMN's dropped similarly to 710 +/- 320, 2390 + 1240 and 3130 +/- 1050 cells/mm3 respectively (p less than 0.05; DAZ vs. BW and placebo). The drop in WBC's predominantly resulted from proportional decreases in PMN's (DAZ: r = 0.98; BW: r = 0.88; placebo r = 0.93). Compared to GBS alone, DAZ reduced pulmonary vasoconstriction, but exacerbated the granulocytopenia. BW755C similarly reduced pulmonary hypertension: however, it ameliorated the exacerbation of GBS induced neutropenia described above. These data imply that there is no direct correlation between GBS induced granulocytopenia and pulmonary hypertension.
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PMID:Prostanoid inhibition and group B hemolytic streptococci (GBS) induced neutropenia in newborn piglets. 212 31

Polymorphonuclear leukocytes isolated from endotoxin pretreated (0.1 mg/kg 24 hours before) guinea pigs are shown to be hypersensitive and hyperresponsive to the formylated bacterial chemoattractant FMLP in vitro. Dose-response curves for chemiluminescence and beta-glucuronidase release are shifted to the left and maxima are increased. In receptor binding studies the FMLP binding capacity is shown to be enhanced in cells from endotoxin pretreated animals. FMLP (0.3 mg/kg) administered intravenously into anaesthetized and artificially ventilated guinea pigs is shown to induce neutropenia and a biphasic rise of the insufflation pressure. This response is exaggerated in endotoxin pretreated animals. The initial elevation of the airway resistance is cyclooxygenase dependent, whereas the following rise is cyclooxygenase independent and parallels the neutropenia. Histologically PMN's are shown to be trapped in the pulmonary capillaries. This is associated with an intraseptal/interstitial edema. The results illustrate a functional synergism between two important bacterial products, endotoxin and FMLP.
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PMID:Endotoxin pretreatment enhances neutrophil FMLP-receptor binding and activity in guinea pigs. 311 69

Hemodynamic and hematologic changes occurring after intravascular complement activation have implicated the anaphylatoxins in this response. In this study, the hemodynamic and hematologic effects of purified C5a were investigated in rabbits; and involvement of prostanoids, histamine, and polymorphonuclear leukocytes (PMNs) were examined. The anaphylatoxin C5a induces a reversible systemic arterial hypotension which coincides with an increase in central venous pressure (CVP), decreased cardiac output (CO), increased plasma prostanoid levels, as well as neutropenia. Total peripheral resistance (TPR) remained unchanged. The cyclooxygenase inhibitor indomethacin abolished the C5a-induced hypotension and normalized plasma prostanoid levels without altering the C5a-induced neutropenia. The thromboxane (Tx) A2 synthetase inhibitor dazoxiben reduced TxB2 plasma levels and increased 6-keto-prostaglandin PGF1 alpha and PGE2 levels without altering the hypotensive response. However, with dazoxiben treatment both TPR and CVP decreased. The H2-receptor antagonist cimetidine reduced C5a-induced hypotension and diminished prostanoid release. Both the hypotensive response and elevated prostanoid release were observed after C5a challenge in animals rendered neutropenic prior to challenge. It is concluded that C5a-induced arterial hypotension in the rabbit is a PMN-independent reaction, mediated through cyclooxygenase products and, to some degree, by histamine. The mechanism producing systemic arterial hypotension does not seem to involve peripheral vasodilation but appears to be a secondary effect of pulmonary vasoconstriction, possibly mediated by TxA2.
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PMID:C5a-induced hemodynamic and hematologic changes in the rabbit. Role of cyclooxygenase products and polymorphonuclear leukocytes. 311 10

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

Trans-2,5-bis-(3,4,5-trimethoxyphenyl)tetrahydrofuran (L652, 731), a potent and specific receptor antagonist of platelet activating factor (PAF) (Hwang et al., J. Biol. Chem. 260: 15639-15645, 1985), potently inhibits several PAF-induced in vivo responses in rats. Intravenously and p.o. administered L-652,731 gave a dose-response inhibition of PAF-induced lysosomal hydrolase secretion and extravasation with ED50 values of 1 and 3 mg/kg, respectively. Inhibitions of 87% were achieved with 50 mg/kg p.o. After a single 5-mg/kg p.o. dose, L-652,731 achieved 50 to 60% inhibition of PAF-induced lysosomal hydrolase secretion and extravasation by 0.5 to 1.5 hr with near maximum inhibition lasting through 6 hr. A 20-mg/kg p.o. dose of L-652,731 inhibited PAF-induced leukopenia and neutropenia by 96 and 73%, respectively. The most substantial inhibitions of the extravasation and lysosomal hydrolase secretion induced by PAF or soluble immune complexes were achieved by p.o. L-652,731 (20 mg/kg) with moderate inhibition by dexamethasone and little or no inhibition by antagonists/inhibitors of histamine H1 or H2 or serotonin receptors or cyclooxygenase. Intravenous infusion of a 0.4 mg of L-652,731 bolus inhibited the hypotensive responses from subsequent PAF infusions by a maximum of 72% and with a half-life duration of action of 2.5 hr. Intravenous infusion of L-652,731 results in an immediate 87% reversal of the extreme hypotension induced by a previous endotoxin injection. Thus, with its good p.o. activity, long duration of action and specificity in inhibiting PAF-induced responses in vivo, L-652,731 is a very useful tool in determining the role of PAF in mediating different pathophysiological processes.
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PMID:Inhibition of the platelet activating factor (PAF)-induced in vivo responses in rats by trans-2,5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (L-652,731), a PAF receptor antagonist. 379 43

Arachidonic acid is metabolized to prostaglandins and thromboxane via the cyclooxygenase pathway and to leukotrienes B4, C4, D4, and E4 via the lipooxygenase pathway. A possible role played by leukotrienes in cardiogenic shock resulting from anaphylaxis prompted us to investigate the action of these compounds on coronary vessels and myocardial contractility. In this study leukotriene B4 (LTB4) and C4 (LTC4) were injected directly into the left circumflex (LCx) coronary artery of nine anesthetized Suffolk sheep. LTB4 had no effect on coronary artery blood flow or myocardial contractility, but 3 X 10(-9) mole induced profound transient circulating neutropenia, reflecting the potent chemotactic and chemokinetic properties of this compound. Injecting as little as 1.6 X 10(-11) mole of LTC4 caused a 14.5 +/- 4.3% (mean +/- SE) reduction of LCx coronary artery flow while 1.6 X 10(-10) mole caused a 26.5 +/- 3.7% decrease of LCx coronary artery flow and an 18.1 +/- 3.2% decrease in systolic shortening of the myocardial region supplied by the LCx coronary artery. Since the decrease in systolic shortening was far greater than that expected on the basis of the reduction in coronary artery flow, we postulate that LTC4 has a direct negative inotropic effect. FPL 55712, a receptor antagonist of leukotrienes C4, D4, and E4, blocked the vasoconstriction induced by LTC4 but only partially blocked the negative inotropic effects of LTC4. LTC4 is a potent vasoconstrictor and negative inotropic agent and may play an important role in anaphylactic shock.
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PMID:Effects of leukotrienes B4 and C4 on coronary circulation and myocardial contractility. 630 44

Platelet activating factor is a multifaceted mediator of inflammation capable of stimulating platelet aggregation as well as anaphylaxis, neutropenia and numerous other in vitro and in vivo cellular changes. This lipid mediator, or autocoid, is released by a wide variety of inflammatory cells following an equally diverse group of cellular stimuli including phagocytosis or antigenic stimulation. The synthesized form of PAF is acetyl glyceryl ether phosphorylcholine (AGEPC). In this study AGEPC aggregated bovine platelets in a dose dependent manner. Maximal, irreversible aggregation occurred at 3.6 X 10(-11) M AGEPC with unwashed platelets and at 8.8 X 10(-12) M AGEPC with washed platelets. Aggregation failed to occur when platelets were tested with the biologically inactive structural analog of AGEPC. The possible contribution by platelet cyclooxygenase products was eliminated by showing lack of platelet aggregation to arachidonic acid and also by pretreating platelets with aspirin.
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PMID:Aggregation of bovine platelets by acetyl glyceryl ether phosphorylcholine (platelet activating factor). 643 5

We compared physiological and ultrastructural indices of acute lung injury (ALI) during septic shock caused by taxonomically diverse pathogens to distinguish ALI due to endogenous inflammatory mediators vs. microbial exotoxins or other factors. Conscious rats were infected i.v. with gram-negative Escherichia coli (EC, serotype 055:B5), exotoxin-C producing gram-positive Staphylococcus aureus (SA), or yeast-phase Candida albicans (CA, a clinical isolate). Viable inocula of 10(10) EC, 10(10) SA, or 10(9) CA caused lethal shock in < 24 h, but distinct types of ALI were noted after bacteria vs. fungi. Within 0.5 h of EC infection, leukocytes marginated in the lung vasculature; by death at 6-14 h, animals were hyperoxemic but not acidemic, and showed slight interstitial edema with increased wet/dry weight ratios (W/D = 5.22 +/- 0.10, mean +/- SE, vs. 4.86 +/- 0.07 in controls, P < 0.05). Similarly mild ALI occurred after 10(10) SA. In contrast, within 0.5 h of CA infection, yeast were visible within lung intravascular leukocytes. By death at 6-12 h, CA animals showed hyperoxic acidemia and moderate ALI with capillary obstruction, interstitial hemorrhage, and elevated lung W/D (5.52 +/- 0.13, P < 0.01 vs. controls) associated with yeast-mycelial transformation. Prior neutropenia accelerated mortality and worsened ALI after CA, with hypoxemic acidemia, increased lung W/D (7.23 +/- 0.34, P < 0.05 vs. other groups), capillary occlusion, perivascular and alveolar hemorrhage, and septal disruption by mycelia. Bacteremia induced large increases in serum tumor necrosis factor-alpha (TNF) and interleukin-1 alpha within 1.5 h, but these cytokines remained low in CA animals, even at death. Neither survival nor ALI after EC or CA was altered by pentoxifylline, which attentuated TNF production, or by cyclooxygenase inhibition with ibuprofen. Thus, overall ALI severity correlated with physiological indices of pulmonary function, but ultrastructural changes correlated better with pathogen type than circulating cytokine or eicosanoid mediators. Whereas lethal bacteremia induced early cytokinemia and mild ALI with or without bacterial exotoxins, moderate ALI apparently was mediated by fungal exotoxins during lethal candidemia, which worsened during neutropenia due to enhanced mycelial proliferation.
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PMID:Acute lung injury during bacterial or fungal sepsis. 828 90


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