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PubMed1994

[Inhibitory effects of exogenous eicosapentaenoic acid on generation of leukotriene C4 and leukotriene B4 by human leukocytes stimulated with calcium ionophore].

Effects of exogenous eicosapentaenoic acid (EPA) and arachiodonic acid (AA) on generation of leukotriences C4, C5, B4 and B5 were assessed in human leukocytes stimulated with calcium ionophore A23187. Human leukocytes were obtained from healthy volunteers using the dextran sedimentation of peripheral blood and stimulated with 1 microgram/ml calcium ionophore A23187 in the absence or presence of EPA (1-30 micrograms/ml) and/or AA (1-30 micrograms/ml). Leukotriences from leukocytes samples were separated and quantitated by reverse phase high performance liquid chromatography. Mean generation of LTC4 in the absence of fatty acid was 78.2 +/- 25.4 ng/10(7) cells (Mean +/- SD, n = 6). In the presence of EPA, the generation of LTC4 increased a little but significant (p < 0.05) to 85.3 +/- 24.2 ng/10(7) cells at low dose (1 microgram/ml) of EPA, and then decreased to 39.7 +/- 23.4 ng/10(7) cells at high dose (30 micrograms/ml) of EPA (p < 0.05). LTB4 generation was 213.2 +/- 38.0 ng/10(7) cells without fatty acids, and decreased to 174.0 +/- 48.0 ng/10(7) cells at 30 micrograms/ml EPA (p < 0.05). LTC5 and LTB5 production were detectable at 1 microgram/ml EPA and reached to maximum at 10 micrograms/ml EPA with 21.9 +/- 15.6 ng/10(7) cells and 21.8 +/- 7.1 ng/10(7) cells, respectively. Total LTC (LTC4 + LTC5) generation with high dose of EPA (57.2 +/- 28.0 ng/10(7) cells) decreased significantly compared with that in the absence of fatty acids (78.2 +/- 25.4 ng/10(7) cells). At 10 micrograms/ml of AA, both LTC4 and LTB4 generation significantly increased to 114.2 +/- 5.3% and 129.0 +/- 9.5% of control, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

The influence of fibrinogen and fibrin on thrombin generation--evidence for feedback activation of the clotting system by clot bound thrombin.

In plasma the bulk of thrombin generation takes place after a clot has formed. We therefore investigated in what way the clot influences thrombin generation in plasma. The forming clot withdraws thrombin from free solution. Consequently less thrombin activity is found and less thrombin-inhibitor complexes are formed. The thrombin that is adsorbed to the clot reduces the lag time before thrombin generation in intrinsically or extrinsically triggered platelet poor plasma as well as in platelet rich plasma. We investigated the mechanism of this activation. Clots were obtained by recalcification of plasma or by the addition of thrombin-like enzymes (Reptilase, Agihal) from snake venoms. They were thoroughly washed until the washing fluid was devoid of any detectable clotting enzyme activity. In platelet poor plasma (PPP), thrombin-induced clots shorten the factor Va-dependent lag-time of thrombin generation in the extrinsic system as well as the factor VIIIa-dependent thrombin generation in the intrinsic system. Factor V or factor VII preparations that in itself hardly influence thrombin generation patterns acquire the capacity to shorten these lag-times when incubated with clot. The last washing fluid of the clot is inactive. Snake venom induced clots are not active either. Clots that are incubated in heparinised plasma for 1 h or more are as active as clots from normal plasma are. A role of factor Xa can not be excluded but must be minor because a clot made by addition of thrombin to plasma from which the factors II, VII, IX and X have been removed is as active as a clot from normal plasma is.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗
PubMed1994

Effects of anti-allergy drugs on fMet-Leu-Phe-stimulated superoxide generation in human neutrophils.

We examined effects of six oral anti-allergy drugs used to treat bronchial asthma on fMet-Leu-Phe (N-formyl-methionyl-leucyl-phenylalanine)-induced superoxide (O2-) generation and mobilization of intracellular free calcium ([Ca2+]i) in human neutrophils. We also evaluated the direct action of these drugs on NADPH (reduced nicotinamide-adenine dinucleotide phosphate)-oxidase activity in cell lysate (cell-free system). Ketotifen (25 approximately 200 microM) enhanced fMet-Leu-Phe-stimulated O2- generation and [Ca2+]i mobilization, although it directly inhibited NADPH oxidase in the cell-free study. Low concentrations of oxatomide (5-20 microM) enhanced O2- generation, but concentrations > 25 microM inhibited O2- generation. In concentrations below 20 microM, oxatomide had no effects on fMet-Leu-Phe-stimulated [Ca2+]i mobilization, but at concentrations above 25 microM, it inhibited [Ca2+]i mobilization. Oxatomide inhibited NADPH oxidase activity at all concentrations examined. Azelastine, pemirolast, tranilast, and repirinast inhibited O2- generation and [Ca2+]i mobilization. Azelastine and pemirolast directly inhibited NADPH oxidase, but tranilast and repirinast did not. Our results indicated that except for ketotifen and low concentration of oxatomide, oral anti-allergy drugs used to treat bronchial asthma inhibited fMet-Leu-Phe-induced O2- generation in human neutrophils. Based on IC50 values, potency of drugs was as follows: oxatomide > azelastine > tranilast > pemirolast > repirinast.

Adult↗
PubMed1994

Establishment of a human system that generates O2- and induces 8-hydroxydeoxyguanosine, typical of oxidative DNA damage, by a tumor promotor.

We have established a system in which a human cell line generated reactive oxygen species (ROS), using a dimethyl sulfoxide-differentiated promyelocytic leukemia cell line HL60 (DMSO-HL60), which has characteristics similar to those of human neutrophils. DMSO-HL60 generated O2- upon stimulation with a tumor promoter, phorbol myristate acetate (PMA). O2- generation, determined as O2- release from the PMA-stimulated cells by the reduction of cytochrome c, was dependent on the dose of PMA and reached almost maximal with 2.0 nM PMA. PMA dose-dependently increased 8-hydroxydeoxyguanosine (8OHdG) in DMSO-HL60, typical of mutagenic oxidative DNA damage. The 8OHdG level, determined by electrochemical detection with high performance liquid chromatography, also became almost maximal with 2.0 nM PMA. The amount of O2- generation and that of the 8OHdG induction by PMA in human neutrophils were similar to those in DMSO-HL60. Superoxide dismutase inhibited the 8OHdG induction by about 60%, whereas catalase, deferoxamine, or thiols inhibited it almost completely. Dilution of PMA-stimulated DMSO-HL60 decreased the concentration of ROS releasing to the media from the cells. However, it did not decrease the ROS generation per cell or the 8OHdG induction. The addition of H2O2 to unstimulated DMSO-HL60 did not increase the 8OHdG level. These findings indicate that DMSO-HL60 could be used as a substitute for human neutrophils, that the concentration of ROS is not the only determinant for the 8OHdG induction, but that it requires both acquisition of susceptibility to ROS by reduction of iron by O2- and formation of H2O2, and that ROS increase 8OHdG by attacking the ROS-generating cell.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1994

Long chain acyl coenzyme A and signaling in neutrophils. An inhibitor of acyl coenzyme A synthetase, triacsin C, inhibits superoxide anion generation and degranulation by human neutrophils.

Ligand-initiated activation of neutrophils triggers O2- generation, degranulation, phospholipid remodeling, and release of fatty acids such as arachidonate, oleate, and palmitate. Long chain acyl-CoA synthetase converts free fatty acids to acyl-CoA esters; a role for acyl-CoA esters as positive modulators of neutrophil functions is proposed. Physiologically relevant concentrations (1-10 microM) of acyl-CoA esters such as palmitoyl-CoA, enhanced O2- generation triggered by fMet-Leu-Phe or guanosine 5'-O-(thiotriphosphate) (GTP gamma S) but did not act as a trigger per se. Triacsin C, an inhibitor of acyl-CoA synthetase, inhibited fMet-Leu-Phe-elicited O2- generation and degranulation in a concentration-dependent manner. Triacsin C inhibited O2- generation elicited by fMet-Leu-Phe and GTP gamma S in electroporated neutrophils, indicating that acyl-CoA acted downstream from the receptor. Palmitoyl-CoA reversed the Triacsin C-induced inhibition of O2- generation. fMet-Leu-Phe elicited a prompt increase in total long chain acyl-CoA esters. Arachidonoyl-CoA and oleoyl-CoA were elevated 5 s after addition of fMet-Leu-Phe, while palmitoyl-CoA was not elevated until 60 s. Triacsin C inhibited fMet-Leu-Phe-initiated increases in arachidonoyl-CoA, oleoyl-CoA, and palmitoyl-CoA. These results suggest a role for acyl-CoA esters in regulating activation of O2- generation and degranulation at the G protein or subsequent step(s).

Acyl Coenzyme A↗
PubMed1994

Monocyte dysfunction in patients with Gaucher disease: evidence for interference of glucocerebroside with superoxide generation.

Gaucher disease patients are occasionally affected by chronic or fulminant infections. Since Gaucher cells originate from tissue phagocytes, we studied the functional implications of glucocerbroside accumulation on phagocytes in Gaucher disease patients. Circulating monocytes and granulocytes from nine type I Gaucher disease patients, and matched controls, were studied. Evaluation of phagocytic activity included (1) maximal superoxide generation rates following stimulation by phorbol 12-myristate 13-acetate (PMA), opsonized zymosan (OZ), or formyl-methionyl-leucylphenylalanine (FMLP); (2) nitroblue tetrazolium reduction test (NBT); (3) chemotaxis toward FMLP; (4) phagocytosis of OZ particles; and (5) killing activity against Staphylococcus aureus. Superoxide generation in monocytes following PMA, OZ, and FMLP stimulation was significantly suppressed at 52% +/- 15%, 39% +/- 8%, and 51% +/- 11% of control, respectively. Superoxide generation in granulocytes was normal. NBT reduction, staphylococcal killing, and phagocytosis were also markedly decreased in monocytes, and normal in granulocytes. Mean chemotaxis rates were normal in both monocytes and granulocytes; however, decreased chemotactic rates were observed in some patients. The abnormality of superoxide generation could be reproduced in a dose- and time-dependent manner in normal circulating monocytes incubated with glucocerebroside. Superoxide generation in glucocerebroside-conditioned normal monocytes in a cell-free system showed normal superoxide generation, reflecting the integrity of the NADPH oxidase complex itself. These results demonstrate markedly compromised phagocytic functions in circulating monocytes in Gaucher disease patients. These abnormalities can be attributed to accumulation of glucocerebroside, since it could be reproduced in normal monocytes incubated with glucocerebroside. Similar abnormalities in Gaucher cells throughout the reticuloendothelial system could impair host defense, and may be of particular importance in the pathogenesis of osteomyelitis in Gaucher disease patients.

Adult↗
PubMed1994

Compensating for changes in muscle length in total hip arthroplasty. Effects on the moment generating capacity of the muscles.

Alterations in the location of the hip center may change the lengths and moment arms of the muscles, and thereby affect their capacity to generate force and moment about the hip. This study demonstrates some of the differences between compensating and not compensating for changes in muscle length that arise from displacement of the hip center. A computer model was developed to estimate the maximum isometric moment generating capacity of the hip muscles under two conditions. In the compensated condition, the hip center was displaced, but the muscles were restored to their original lengths and orientations by altering proximal femoral geometry. In the uncompensated condition, femoral geometry remained constant; thus, muscle lengths and orientations changed with displacement of the hip center. The computer simulations showed large differences between the two conditions. For example, a 2-cm superior displacement of the hip center decreased the moment generating capacity of the hip abductors 18% with compensation and 49% without compensation. Similarly, a 1-cm medial displacement of the hip center increased the moment generating capacity of the abductors 17% with compensation, but decreased it 4% without compensation. In contrast, a 1-cm inferior displacement decreased the moment generating capacity of flexors 6% with compensation, but increased it 12% without compensation. The results presented here demonstrate that compensating for changes in muscle length can be important in terms of preserving the moment generating capacity of the muscles when the hip center is displaced superiorly and medially, but not when the hip center is displaced in the inferior direction.

Adaptation, Physiological↗
PubMed1994

[Antidepressives of the 3rd, 4th and 5th generation].

Antidepressants are classified into five generations. Preparations of the first generation affect various neurotransmitter systems and are therefore associated with many undesirable effects (e.g. tricyclic antidepressants, maprotiline). The second generation of antidepressants is already devoid of anticholinergic action and their adrenolytic and antihistaminic effects are weaker (e.g. mianserine, mirtazapine, trazodone). The antidepressant action of preparations of the third generation is mediated only by one of the three main neurotransmitter systems for depression (5-HT, noradrenaline, dopamine) and does not affect muscarine, histamine and adrenergic cerebral systems (e.g. SSRI, ipsapirone, viloxazine, reboxetine, bupropione). Recently antidepressants of the fourth generation were synthetized which influence only the serotonin, and noradrenaline or dopamine system (e.g. milnacipran, befloxatone). The fifth generation of antidepressants foresees the exclusive action on 5-HT, noradrenaline and dopamine systems of the CNS in varying ratios (e.g. venlafaxine, cericlamine).

Antidepressive Agents↗
PubMed1993

Electron spin resonance spin-trapping investigation into the effects of paraquat and desferrioxamine on hydroxyl radical generation during acute iron poisoning.

We have previously described a secondary radical-trapping technique for the detection of in vivo hydroxyl radical generation during acute iron overload. With this technique, the hydroxyl radical (.OH) reacts with dimethylsulfoxide to form the methyl radical (.CH3), which is then detected by ESR spectroscopy as its adduct with the spin trap phenyl-N-tert-butylnitrone in the bile of treated animals. In this study, we report both the individual and combined effects of the futile-cycling agent paraquat (PQ2+) and the iron-chelating agent desferrioxamine (DFO) on iron-dependent .OH generation. Interactions between iron and the partially reduced oxygen species superoxide and hydrogen peroxide, which are generated during the metabolism of PQ2+, might be expected to stimulate .OH generation to a level above that seen in the presence of the metal ion alone. Although PQ2+ was often found to promote further .OH generation when administered to animals also given iron, the large variation observed between individual animals in response to the reagent meant that the effect was not statistically significant (p < 0.05). DFO was found to abolish iron-dependent .OH generation, both in the presence and in the absence of PQ2+. This is believed to result from the chelation of iron by DFO, to form an essentially redox-inert iron(III) complex that is unable to catalyze .OH radical formation. In addition, it was found that the iron(II) complex of DFO can reduce PQ2+ to its radical cation in vitro, indicating, therefore, that the chelation of iron by DFO may not necessarily prevent its participation in free radical reactions.

Animals↗
PubMed1993

Fixation of C3 to IgG attenuates neutrophil HOCl generation and collagenase activation.

Neutrophils stimulated with surface-associated monomeric IgG (SAIgG) release an activated collagenase in association with significant generation of hypochlorous acid (HOCl). To determine whether these neutrophil responses are modulated by IgG C fixation, neutrophils were incubated with SAIgG pretreated with normal or C-deficient sera. Treatment of SAIgG with normal sera did not attenuate neutrophil superoxide production, H2O2 generation, or extracellular release of latent collagenase and lactoferrin; however, serum treatment resulted in significant attenuation of SAIgG-induced HOCl generation (75%) and extracellular release of the azurophilic granule constituents myeloperoxidase and cathepsin G. Collagenase activity in supernatants of neutrophils incubated with SAIgG pretreated with normal sera (9.5 +/- 0.8 ng/min) was significantly less than activity in supernatants of neutrophils incubated with SAIgG not treated with sera (15.3 +/- 1.2 ng/min). Treatment of surface adherent monoclonal IgG1 and IgG2 with sera resulted in significantly greater attenuation of HOCl generation compared to serum treatment of IgG4. Attenuation of HOCl generation was not observed when SAIgG was pretreated with heat-inactivated sera, EDTA-chelated sera, or sera depleted of C3; treatment of SAIgG with C5-depleted sera yielded results comparable to treatment with intact sera. These results indicate that C3-derived ligands fixed to adherent Ig alter IgG-induced release of azurophilic granule constituents and HOCl generation by neutrophils.

Antigen-Antibody Complex↗
PubMed1977

Relationship of cellular proliferation and the generation of cytotoxic cells in an in vitro secondary immune response to syngeneic rat lymphoma cells.

The role of cellular proliferation for the generation of cytotoxic activity in an in vitro secondary immune response to syngeneic lymphoma cells was investigated. Spleen cells from W/Fu rats immunized with the syngeneic (C58NT)D tumor proliferate and generate cytotoxic potential for tumor targets after exposure to mitomycin C-treated (C58NT)D cells in vitro. Elimination of proliferating cells by exposure to high specific activity 3H thymidine at approximate intervals impaired the generation of cytotoxic activity. Elimination of cells proliferating to either syngeneic lymphoma or BN rat alloantigens allowed the remaining cells to generate cytotoxic potential to the second set of antigens. Elimination of proliferating cells also abrogated the ability of the in vitro generated cells to adoptively confer anti-tumor protection on nonimmune recipients. These results demonstrate that cellular division is required for the generation of cells which are cytotoxic in vitro and can adoptively confer anti-tumor protection in vivo.

Animals↗
PubMed1993

Effects of exogenous eicosapentaenoic acid on generation of leukotriene C4 and leukotriene C5 by calcium ionophore-activated human eosinophils in vitro.

Exogenous eicosapentaenoic acid (EPA) has been compared with exogenous arachidonic acid (AA) for its ability to modulate the oxidative metabolism of membrane-derived arachidonic acid by the 5-lipoxygenase pathway in ionophore-activated human eosinophils, and for its suitability as a parallel substrate in this pathway. Products were quantitated by specific RIA and tetraene and pentaene leukotrienes (LT) were separated by reverse-phase HPLC. Eosinophils were preincubated with control buffer, exogenous EPA or AA and stimulated optimally with 10 microM calcium ionophore (A23187) for 15 min. Mean generation of LTC4 in the absence of fatty acid was 6.0 = 1.1 ng/10(6) eosinophils (mean = SEM, n = 5). In the presence of EPA, the amount of LTC4 generated rose to peak at 16.5 +/- 1.9 ng/10(6) eosinophils at 10 micrograms/ml EPA and then fell to 8.3 +/- 3.1 ng/10(6) cells at 40 micrograms/ml EPA. The EPA derivative, LTC5 was first detectable at 5 micrograms/ml EPA with 4.8 +/- 1.2 ng/10(6) cells and gradually rose with increasing dose of EPA to be maximal at 40 micrograms/ml with 12.7 +/- 2.2 ng/10(6) cells. Identity of the LTC5 was confirmed by an identical retention time to synthetic LTC5 standard, immunoreactivity to a specific antibody against LTC4 and LTC5 and a typical UV absorbance spectrum. When eosinophils were preincubated with AA and similarly stimulated, LTC4 generation gradually increased from a baseline of 6.7 +/- 0.7 ng/10(6) cells in the absence of fatty acid to reach a maximum of 12.9 +/- 0.8 ng/10(6) cells at 40 micrograms/ml of AA. Total LTC generation was nearly twofold more with cells incubated with EPA than with cells incubated with AA (p < 0.05). Thus, EPA does not suppress LTC generation from eosinophils but stimulates it at lower doses and is a substrate for LTC5 generation.

Arachidonic Acid↗
PubMed1993

Platelet-activating factor-induced human eosinophil activation. Generation and release of cyclo-oxygenase metabolites in human blood eosinophils from asthmatics.

The spontaneous and stimulated generation of fatty acid cyclo-oxygenase pathway-derived products of arachidonic acid from highly purified (91.6 +/- 1.3%, n = 23) human blood eosinophils obtained from asthmatics were examined using combined gas chromatography/mass spectrometry. Under resting conditions, eosinophils spontaneously generated 0.24 +/- 0.10 pg prostaglandin E2 (PGE2), 0.51 +/- 0.20 prostaglandin D2 (PGD2), 0.35 +/- 0.10 pg prostaglandin F2 alpha (PGF2 alpha) and 8.5 +/- 2.2 pg thromboxane B2 (TXB2), the stable metabolite of TXA2 per 10(6) cells. In contrast, 6-keto-prostaglandin F1 alpha and 9 alpha,11 beta-prostaglandin F2 were not detectable. Stimulation of eosinophils with platelet-activating factor (PAF) for 5 min induced a two- to sixfold increase in the biosynthesis of prostanoids. More than 95% of the generated prostanoids were released into the surrounding medium. The response to PAF was inhibited by the PAF receptor antagonist WEB 2086 (1 microM). The fatty acid cyclo-oxygenase inhibitor, ibuprofen, abolished both the spontaneous and PAF-stimulated generation of prostanoids by eosinophils. LTB4, PMA and calcimycin also produced an increase in prostanoid production, whereas lyso-PAF, the PAF precursor and metabolite, failed to induce prostanoid generation over basal production. In conclusion, the results demonstrate that PAF potently activates human eosinophils to generate and release several fatty acid cyclo-oxygenase metabolites of the arachidonic acid pathway, with TXB2 being the most abundant. These data are in agreement with previous observations suggesting that PAF may be an important stimulus for prostanoid release by the eosinophil in allergic diseases such as asthma.

Asthma↗
PubMed1995

CD4 Th2 cells do not functionally suppress CTL generation in neonatal tolerant mice.

Injecting semiallogeneic CAF1 spleen into BALB/c newborn mice renders mice tolerant, and the majority of mice show prolonged survival of tolerogen-bearing A/J skin grafts. Moreover, graft survival is associated with enhanced Th2 cytokine responses and graft rejection with Th1 cytokine responses. To further delineate the mechanisms of tolerance, we evaluated CTL responses and found that 74% of neonatal primed mice failed to generate A/J-specific CTL responses, as determined by standard CTL assays and pTc3 frequency analyses. CTL unresponsiveness coexisted with an enhanced tolerogen-specific Th2 memory cytokine profile; spleen cells from neonatal primed mice secreted more interleukin (IL)-4 and less IL-2 and interferon (IFN)-gamma in MLR cultures compared with either adult primed or naive controls. We therefore examined the hypothesis that enhanced Th2 cytokine levels prevent the generation of tolerogen-specific CTL. Adding neutralizing antibodies to IL-4 and IL-10 recovered IFN-gamma production in vitro but not A/J-specific CTL response. In addition, CD4 cells from neonatal primed mice provided help for primary or secondary CD8 CTL generation, which suggests that the enhanced Th2 cytokine profile does not actively suppress CTL generation. Furthermore, CD4 cells from adult primed mice failed to restore the A/J-specific CD8 CTL generation of neonatal primed mice. The results show that failure to develop A/J-specific CTL reaction occurs without suppression by the enhanced Th2-type responses and imply that either deletion or anergy mechanisms block CTL generation. Therefore, neonatal alloantigen exposure not only shifts the development of alloreactive CD4 cells toward Th2, but also blocks development of alloreactive CD8 CTL in this strain combination.

Animals↗
PubMed1977

A neutrophil-dependent pathway for the generation of a neutral peptide mediator. II. Subcellular localization of the neutrophil protease.

The human neutrophil neutral peptide-generating protease was associated with the plasma membrane marker 5'-nucleotidase on sucrose density gradient centrifugation of sonicates of granule-free fractions following homogenization and velocity sedimentation. The two activities were also associated on sucrose density gradient fractionation of plasma membranes obtained by hypotonic lysis in EDTA containing buffers, a technique which minimizes aggregation. Treatment of fractions containing these enzymatic activities with 1-0 M NaCl separated the neutral peptide-generating proteasein to the eluate while leaving the 5'-nucleotidase in the pellet. Gel filtration of the solubilized neutral peptide-generating protease through Sephadex G-100 in 1-0 M NaCl demonstrated that the protease had an approximate mol. wt of 20,000 while filtration in physiological salt concentrations yielded activity only in the excluded volume. In both cases, there was complete recovery of neutral peptide-generating activity suggesting that the filtration characteristics of the protease were determined by the salt concentration. The solubilized purified protease, the whole cell sonicates, and the intact cells interacted with heat-inactivated plasma to yield the same product, a neutral peptide with a 1000 molecular weight and an isoelectric point of 7-2-7-6. The neutral peptide-generating protease in each instance was inhibited in dose-response fashion by alpha-1-antitrypsin, LBTI, and DFP. Only 30-60% of the protease sites were functional on intact cells as revealed by substrate cleavage or were available to inhibitors. The neutrophil protease which generates neutral peptide is an extrinsic plasma membrane protein with an approximate mol. wt of 20,000 which functions as an ectoenzyme.

Cell Fractionation↗
PubMed1996

Effects of dithranol on neutrophil superoxide generation in patients with psoriasis.

The effect of dithranol on superoxide generation in vivo has not been studied previously. Neutrophils produce large amounts of superoxide following stimulation by phorbol 12-myristate-13-acetate (PMA). We studied the effect of dithranol on PMA-activated superoxide generation by isolated neutrophils from normal subjects, and measured whole blood luminescence in response to PMA, using samples from 13 psoriatic patients before and during dithranol treatment. Oxidized dithranol had no effect on the PMA-stimulated superoxide generation in neutrophils, but there was a modest dose-related increase in superoxide generation by neutrophils exposed to dithranol before activation. Similar results were found with neutrophils obtained from the 13 psoriasis patients. Three of these patients suffered a dithranol burn and developed a neutrophilia, with a marked increase in stimulated superoxide generating ability. Our findings suggest that dithranol treatment of a psoriasis plaque is associated with a decrease in oxygen radical generating capacity in vivo. However, where inflammation of perilesional and uninvolved skin occurs, neutrophils appear to become semi-activated or primed.

Administration, Topical↗
PubMed1996

Pharmacological targeting of signaling pathways in protein kinase C-stimulated superoxide generation in neutrophil-like HL-60 cells: effect of phorbol ester, arachidonic acid and inhibitors of kinase(s), phosphatase(s) and phospholipase A2.

The purpose of this investigation was to pharmacologically probe the signaling pathways thought to be involved in protein kinase C (PKC)-stimulated superoxide anion (O2-) generation in all-trans retinoic acid-treated human promyelocytic HL-60 cell line (HL-60), targeting PKC, mitogen-activated protein kinase (MAPK), MAPK kinase (MEK), protein serine-threonine phosphatase(s) (PSP), protein tyrosine kinase(s) (PTK) and phosphatase(s) (PTP), secretory phospholipase A2, cyclooxygenase (CO) and 5-lipoxygenase with selected inhibitors. The following agents inhibited phorbol 12-myristate 13-acetate-stimulated O2- generation significantly in the all-trans retinoic acid-treated HL-60 cells (expressed as percentage of control, P < .05): 1) PKC inhibitors: staurosporine (100 nM, 3 +/- 1%); Ro 31-8220 (1 microM, 3 +/- 2%); sphingosine (100 microM, 15 +/- 7%); 2) PSP 1 and 2a inhibitors, okadaic acid (10 microM, 35 +/- 1%); calyculin A (10 microM, 73 +/- 1%); 3) MAPK inhibitor: SB-203580 (100 microM, 62 +/- 1%); 4) PTP inhibitors: phenylarsine oxide (1 microM, 12 +/- 9%); diamide (1 mM, 21 +/- 11%); and 5) secretory phospholipase A2 inhibitors: manoalide (1 microM, 24 +/- 10%); scalaradial (1 microM, 11 +/- 4%). Exogenously added arachidonic acid-stimulated O2- generation in a time- and dose-dependent manner. The following inhibitors enhanced or did not significantly affect phorbol 12-myristate 13-acetate-stimulated O2- generation (expressed as percentage of control): 1) PTK inhibitors: genistein (100 microM, 69 +/- 12%); CGP 53716 (100 microM, 67 +/- 10%); herbimycin A (10 microM, 67.4 +/- 1%); 2) PSP 2b inhibitors: cyclosporin A (30 microM, 71 +/- 5%); FK506 (30 microM, 88 +/- 7%); 3) CO inhibitor: indomethacin (100 microM, 111 +/- 12%); 4) 5-lipoxygenase inhibitor: WY 50,295 (100 microM, 140 +/- 23%); 5) MEK inhibitor: PD98059 (100 microM, 94 +/- 6.7%); and 6) the PTP inhibitor: orthovanadate (100 microM, 131 +/- 25%). Our pharmacological study suggests that, in neutrophil-like HL-60 cells, the signaling pathways leading to PMA-stimulated O2- generation appear to involve PKC, MAPK, phospholipase A2, arachidonic acid, PSP 1 and 2a and PTP. Furthermore, PTK, MEK, CO, 5-lipoxygenase and PSP 2b do not appear to participate in the modulation of PKC-stimulated O2- generation.

Arachidonic Acid↗
PubMed1996

The item-order distinction and the generation effect: the importance of order information in long-term memory.

The item-order distinction has been useful in explaining memory dissociations in short-term retention tasks. It generally has been assumed that serial order information is beneficial to long-term retention as well, although the distinction has received little empirical attention. Recently, it was shown that generating items at input, rather than simply reading them, hinders processing of serial order information. This reduction in order processing has been implicated in the lack of generation effects in between-list designs. Experiment 1, using typical generation effect procedures, showed that generation inhibited order reconstruction performance. Experiment 2 showed that order reconstruction was hindered even when categorically related lists were used. Experiment 3 demonstrated that generation inhibited order reconstruction in an incidental learning procedure. The results suggest that order processing is relatively automatic and that generation constantly inhibits it. The results support the view that the item-order distinction may be a powerful explanatory tool in long-term memory research.

Adult↗