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1.
R Anderson 《International archives of allergy and applied immunology》1981,65(3):257-265
The effects of levamisole, at concentrations known to stimulate neutrophil motility, on neutrophil post-phagocytic metabolic activity were investigated. Levamisole at these concentrations caused inhibition of hexose monophosphate shunt (HMS) activity, superoxide production, hydrogen peroxide generation and myeloperoxidase (MPO), mediated iodination of ingested Candida albicans,. The inhibition of MPO-mediated iodination was not solely due to lack of H2O availability as a result of decreased HMS activity but also to a primary inhibition of iodination as shown in a cell-free system with horse-radish peroxidase (HRP) and added H2O2 and sodium iodide. Further experiments were designed to investigate possible relationships between stimulation and motility and levamisole-induced inhibition of superoxide generation and peroxidase-mediated iodination. These showed that the peroxidase/halide/H2O2 system caused inactivation of both the leucoattractant and neutrophil chemotactic responsiveness. However, concentrations of levamisole, which stimulate motility and inhibit superoxide production and peroxidase-mediated iodination, protected both the leucoattractant response and the ability of the cell to respond to the leucoattractant from inactivation by the HRP/H2O2/iodide system. 相似文献
2.
The effects of sodium aurothiomalate, levamisole, its active metabolite OMPI and the anti-inflammatory agents indomethacin and tolmetin on neutrophil motility and post-phagocytic hexose monophosphate shunt activity, superoxide and H2O2 generation and myeloperoxidase (MPO) mediated iodination of Candida albicans were investigated in vitro. All five agents caused stimulation of neutrophil random motility and migration towards the leucoattractants f-met-met-phe and EAS. Only levamisole caused inhibition of H2O2 and superoxide production, which was associated with inhibition of HMS activity and not related to superoxide scavenging activity. All five agents caused inhibition of MPO mediated iodination of C. albicans. The relationship between inhibition of peroxidase mediated iodination and enhanced motility was further investigated using the horseradish peroxidase (HRP) H2O2/iodide system. Incubation of neutrophils with this system caused inhibition of neutrophil motility. However in the presence of the various drugs neutrophils were protected from inhibition of motility by the HRP/H2O2/iodide system. Further experiments showed that lymphocyte transformation to mitogens was also inhibited by the HRP/H2O2/iodide system. Incubation of lymphocytes with the various drugs prior to exposure to HRP/H2O2/iodide protected the lymphocyte mitogenic responsiveness. 相似文献
3.
In vitro and in vivo stimulation of neutrophil migration and lymphocyte transformation by thiamine related to inhibition of the peroxidase/H2O2/halide system. 总被引:1,自引:1,他引:1
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The effects of thiamine on neutrophil functions and mitogen-induced lymphocyte transformation were investigated in vitro and in vivo in adult volunteers following the injection of 50 mg thiamine intramuscularly. Thiamine caused stimulation of neutrophil motility in vitro and in vivo and increased lymphocyte transformation in vivo. Enhancement of these functions was related to inhibition of neutrophil post-phagocytic iodination of Candida albicans by the MPO/H2O2/halide system. The horseradish peroxidase/-H2O2/125 I-mediated iodination of bovine serum albumin was also inhibited by thiamine concentrations which caused increased neutrophil motility. It was found that preincubation of neutrophils and lymphocytes with the horseradish peroxidase/H2O2/halide system caused considerable inhibition of the migratory and proliferative responses respectively. Inclusion of thiamine at concentrations which were found to inhibit the peroxidase/-H2O2/halide system protected the neutrophil migratory and lymphocyte proliferative responses from inactivation by this system. It is suggested that thiamine may cause increased neutrophil migration and lymphocyte transformation by protecting these cells from toxic oxidative products generated by the peroxidase/H2O2/halide system. 相似文献
4.
Assessment of oral ascorbate in three children with chronic granulomatous disease and defective neutrophil motility over a 2-year period 总被引:1,自引:1,他引:0
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R Anderson 《Clinical and experimental immunology》1981,43(1):180-188
Two brothers and their sister with chronic granulomatous disease, elevated levels of serum IgE and defective neutrophil motility were treated with a single oral daily dose of 1 g sodium ascorbate as a supplement to prophylactic trimethoprim--sulphamethoxazole therapy for 2 years. Laboratory tests of neutrophil functions were performed prior to ascorbate therapy and repeated at 1-monthly intervals for 6 months and at 6-monthly intervals thereafter. Introduction of ascorbate to the therapeutic regimen was accompanied by slight increases in neutrophil hexose monophosphate shunt activity and staphylocidal activity and good improvement of neutrophil motility in all three children. The improved staphylocidal activity was not due to ascorbate-mediated inhibition of neutrophil or serum catalase activities or to detectable increases in superoxide and H2O2 production or activity of the MPO/H2O2/halide system. Both male children have remained free from obvious infection since ascorbate was added to their therapeutic regimen; their sister has experienced one urinary tract infection during a period when treatment with prophylactic co-trimoxazole and ascorbate was inadvertently stopped. All three children have gained weight. 相似文献
5.
The in vitro effects of propranolol and atenolol on neutrophil motility and post-phagocytic metabolic activity.
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Propranolol at concentrations of 1 x 10(-6) to 1 x 10(-4) M consistently increased neutrophil motility as measured in Boyden chambers. The effects were not due solely to stimulation of random migration and chemokinesis but also of directional motility. Propranolol, over a similar concentration range, caused inhibition of post-phagocytic cell metabolic activity (hexose monophosphate shunt, nitro-blue tetrazolium reduction and protein iodination) without any detectable effect on the ingestion rate of Candida albicans. Atenolol had no effect on any of these neutrophil functions. Both drugs were without effect on glycolysis and intracellular cyclic AMP levels. Propranolol however, at concentrations which stimulated cell motility, caused increased intracellular cyclic GMP levels. It is suggested that propranolol may stimulate neutrophil motility by promoting increased intracellular cyclic GMP levels or by decreasing neutrophil superoxide production. 相似文献
6.
Increased leucoattractant binding and reversible inhibition of neutrophil motility mediated by the peroxidase/H2O2/halide system: effects of ascorbate, cysteine, dithiothreitol, levamisole and thiamine. 总被引:1,自引:1,他引:0
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Human blood neutrophils manifested markedly decreased motility following exposure to the horseradish peroxidase (HRP)/H2O2/halide system in vitro. These cells were protected from this inhibitory effect (of the HRP/H2O2/halide system) by inclusion of concentrations in the reaction system of ascorbate, cysteinee, levamisole and thiamine which stimulate neutrophil migration and inhibit activity of the HRP/H2O2/halide system. The reversible nature of the oxidative inhibition of migration was demonstrated by exposing neutrophils to the HRP/H2O2/halide system for 15 min followed by washing to remove the components of the peroxidative system, and subsequent addition of ascorbate, cystein, levamisole, thiamine and the reducing agent, dithiothreitol. Neutrophils so treated completely recovered normal or increased motility induced by the leucoattractants endotoxin-activated serum or synthetic chemotactic tripeptide f-met-leu-phe. This reversible loss of migratory responsiveness following exposure of neutrophils to the HRP/H2O2/halide system was not associated with decreased cell viability or adherence. However, membrane oxidation was accompanied by increased uptake of radiolabelled f-met-leu-phe and degranulation. The increased leucoattractant uptake was decreased by ascorbate, levamisole and thiamine. These agents also prevented oxidation of the neutrophil membrane by the HRP/H2O2/halide system as measured indirectly by inhibition of iodination. 相似文献
7.
Human eosinophil peroxidase induces surface alteration,killing, and lysis of Mycobacterium tuberculosis
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Borelli V Vita F Shankar S Soranzo MR Banfi E Scialino G Brochetta C Zabucchi G 《Infection and immunity》2003,71(2):605-613
The antimycobacterial role of eosinophil peroxidase (EPO), one of the most abundant granule proteins in human eosinophils, was investigated. Our data indicate that purified EPO shows significant inhibitory activity towards Mycobacterium tuberculosis H37Rv. On a molar basis, this activity was similar to that exhibited by neutrophil myeloperoxidase (MPO) and was both dose and time dependent. In contrast to the activity of MPO, which requires H(2)O(2), EPO also exhibited anti-M. tuberculosis activity in the absence of exogenously added peroxide. Morphological evidence confirmed that the mechanism of action of EPO against mycobacteria differs from that of MPO. While MPO kills M. tuberculosis H37Rv exclusively in the presence of hydrogen peroxide, it does not induce morphological changes in the pathogen. In contrast, EPO-treated bacteria frequently had cell wall lesions and eventually underwent lysis, either in the presence or in the absence of H(2)O(2). 相似文献
8.
Afanas'ev IB 《Medical hypotheses》2006,66(6):1125-1128
Signaling functions of superoxide and hydrogen peroxide in enzymatic phosphorylation/dephosphorylation reactions are now well documented, but their mechanisms are still not always clear. Now we propose the novel signaling mechanisms, by which superoxide and hydrogen peroxide mediate the activation and inhibition of phosphorylation/dephosphorylation catalyzed by protein kinases and protein phosphatases. We suggest that as a powerful nucleophile, superoxide is able to mediate phosphorylation of numerous proteins by protein kinases through the deprotonation of protein serine or threonine residues that sharply accelerates the rates of nucleophilic reaction between kinases and phosphorylating proteins. Furthermore the role of superoxide is enhanced due to its "chain" formation in the O(2)(-)--> PI 3-kinase --> protein kinases --> NADPH oxidase --> O(2)(-) cycle. Furthermore we suggest that hydrogen peroxide signaling in the dephosphorylation reactions by protein phosphatases and in the activation of protein kinases is actually mediated by superoxide formed during the conversion of H(2)O(2) into superoxide by the oxidized superoxide dismutase. This proposal is supported by the high rates of superoxide reactions with an anion of the catalytic cysteine residue of protein tyrosine phosphatases and the inability of hydrogen peroxide to react directly with protein serine and threonine residues in the reactions of protein kinases. Understanding of specific role of superoxide in the reactions catalyzed by protein kinases and protein phosphatases can be of importance for the selection of inhibitors of these enzymes playing a big role in numerous physiological and pathological processes. 相似文献
9.
Stephanie H. Pincus 《Inflammation》1980,4(1):89-106
Leukocyte iodination, which requires the granular enzyme peroxidase, hydrogen peroxide generated by the cell, and an appropriate oxidizable cofactor such as iodide, was studied in guinea pig peritoneal exudates. Eosinophils had an active resting iodination which was increased approximately 10-fold by the addition of serum and zymosan. In contrast, neutrophils had barely detectable resting iodination, but marked stimulation also occurred employing serum and zymosan or preopsonized zymosan. Under all conditions tested eosinophil iodination was significantly greater than neutrophil iodination (P< 0.001). The role of the peroxidase system in iodination was confirmed by inhibition in the presence of 10–3 M azide, cyanide, or aminotriazole. Inhibition by exogenous catalase and facilitation by superoxide dismutase substantiated the role of hydrogen peroxide. Autoradiographic and cell separation studies confirmed that the majority of iodination was cell or particle associated.Dr. Pincus was a Research Associate of the Veterans Administration. Additional support was provided by a fellowship from the Dermatology Foundation and NIH grant 5 K08 AM 00538-02. 相似文献
10.
D Nowak 《Archivum immunologiae et therapiae experimentalis》1988,36(6):723-731
The oxidative inactivation of alpha 1-proteinase (alpha 1AP) inhibitor is a one of mechanisms that may lead to the pulmonary emphysema. This process is caused by oxidants derived from atmosphere and released from lung phagocytes. These cells produce various oxidants hydrogen peroxide (H2O2), hypochlorous acid (HClO), hydroxyl (OH.) and superoxide (O2-) radicals after inflammatory stimulation. In this study I have investigated the effects of H2O2 (1.5 x 10(-5) to 1.5 x 10(-2) M) alone or with addition of FeCl2 (50 microM) in order to generate OH., chloramine-T (1.5 x 10(-5) to 1.5 x 10(-3) M) which generates HClO, glucose 10 mg/ml-glucose oxidase (12.5 to 80 mU/ml)-H2O2 generating system, xanthine 0.2 mM-xanthine oxidase (12.5 to 80 mU/ml)-O2-2 generating system on the elastase inhibitory activity of alpha 1AP in vitro. H2O2 was weak in alpha 1AP inactivation--only concentration of H2O2 1.5 x 10(-2) caused severe loss of its activity to 23 +/- 8% inhibition of elastase. Addition of FeCl2 to H2O2 and following OH. generation did not enhance its alpha 1AP inactivation. O2-2 generating system inhibited moderately alpha 1AP. The % inhibition of elastase at concentration of xanthine oxidase 80 mU/ml was 65 +/- 7. HClO was most effective as an alpha 1AP inactivator. All used chloramine-T concentrations completely suppressed alpha 1AP activity. The obtained results and in vivo consumption of H2O2 by polymorphonuclear leukocyte myeloperoxidase for HClO production suggest that scavenging of these reactive oxygen species may be useful in prevention of emphysema. 相似文献
11.
Engagement of adenosine receptors inhibits hydrogen peroxide (H2O2-) release by activated human neutrophils 总被引:6,自引:0,他引:6
B N Cronstein S M Kubersky G Weissmann R Hirschhorn 《Clinical immunology and immunopathology》1987,42(1):76-85
Adenosine and its analogs, acting at specific cell surface receptors, inhibit generation of superoxide anion by neutrophils. Since it has been suggested that hydrogen peroxide (H2O2) release may not be contingent upon superoxide anion release, we studied the effects of 2-chloroadenosine, a potent adenosine receptor agonist, on the formation of H2O2 by neutrophils exposed to various stimuli: n-formyl-methionyl-leucyl-phenylalanine (FMLP), concanavalin A, phorbol myristate acetate (PMA), serum-treated zymosan particles (STZ), and immune complexes. 2-Chloroadenosine (0.01-10 microM) inhibited formation of H2O2 by neutrophils exposed to FMLP, concanavalin A, and STZ particles. As we have found with O2- generation, 2-chloroadenosine failed to inhibit H2O2 release by neutrophils stimulated by either phorbol myristate acetate or immune complexes. The data show that whereas adenosine and its analogs inhibit neutrophil release of H2O2 and superoxide anion in response to most ligands, they fail to inhibit activation of neutrophils by immune complexes. Nor do they inhibit neutrophil activation by PMA, an agent which bypasses cell surface receptors by direct activation of protein kinase C. Surprisingly, we found that adenosine deaminase activity was adsorbed onto zymosan particles during opsonization and enhanced release of H2O2 by neutrophils exposed to STZ. These studies with yeast cell walls suggest that if microorganisms adsorb adenosine deaminase from serum, then the intracellular microbicidal activity of neutrophils is enhanced. 相似文献
12.
Reactive oxygen intermediates (ROI), nitrite and interferon-gamma (IFN-gamma) production were investigated at different times during treatment in 10 patients with visceral leishmaniasis (VL). Hydrogen peroxide (H2O2), superoxide (O2-) and IFN-gamma production by cultured monocytes from patients with active VL were significantly lower compared with the healthy controls. In contrast, nitrite levels in the supernatants from monocyte cultures of VL patients were comparable to healthy controls and increased significantly during antileishmanial therapy. On day 20 of treatment, a significant increase in the release of H2O2, O2- and IFN-gamma was observed. However, at follow-up, 4 months after the end of treatment, the production of H2O2, O2-, IFN-gamma and nitrite had declined significantly. Thus, the impairment in hydrogen peroxide and superoxide production suggests that down-regulation of these mediators may be involved in the reduced killing of parasites by monocytes of active VL patients. Furthermore, the monocytes regained respiratory burst activity as the antileishmanial therapy progressed, suggesting that an immune-based mechanism is involved in successful drug therapy. 相似文献
13.
目的:研究脂联素(APN)对过氧化氢(H2O2)诱导人脐静脉内皮细胞 (HUVECs) 脂质过氧化的影响。方法:采用Annexin V-FITC标记后流式细胞检测方法观测H2O2引起的细胞凋亡情况。用硫代巴比妥酸微量法测定丙二醛(MDA),黄嘌呤氧化酶法测总超氧化物歧化酶(SOD),可见光法测过氧化氢酶(CAT)。体外自由基捕捉实验检测APN对超氧阴离子和羟自由基的清除率。结果:APN能明显抑制H2O2引起的细胞凋亡。APN预处理HUVECs后,H2O2(200 μmol/L,6 h)所致的细胞膜脂质过氧化反应明显减弱,MDA产生减少,CAT和SOD活性增加,但仅以APN孵育HUVECs对SOD和CAT活性没有明显的影响。结论:结果表明APN对超氧阴离子和羟自由基有明显的清除效果。APN通过抗脂质过氧化发挥抑制细胞凋亡,保护血管内皮细胞抵抗损伤的作用。 相似文献
14.
Comparison of inhibitory effects of local anesthetics on immune functions of neutrophils 总被引:2,自引:0,他引:2
Azuma Y Shinohara M Wang PL Suese Y Yasuda H Ohura K 《International journal of immunopharmacology》2000,22(10):789-796
Immunological effects of a variety of local anesthetics on adhesion, phagocytosis, and the production of superoxide anion and hydrogen peroxide by neutrophils were compared. Neutrophils were isolated by peritoneal lavage from rats, 4 h after injection of 1% glycogen. Lidocaine, mepivacaine, procaine, prilocaine and tetracaine at 1 mg/ml inhibited adhesion, phagocytosis, and the production of superoxide anion and hydrogen peroxide in neutrophils. Moreover, lidocaine, mepivacaine, procaine and prilocaine at 0.1 mg/ml inhibited the production of superoxide anion and hydrogen peroxide but not adhesion or phagocytosis. In contrast, tetracaine at 0.1 mg/ml inhibited phagocytosis, and the production of superoxide anion and hydrogen peroxide but not adhesion. At 0.01 mg/ml, however, tetracaine inhibited the production of superoxide anion and hydrogen peroxide; in contrast, other drugs failed to affect neutrophil function. These results suggest that the local anesthetics may affect adhesion, phagocytosis, and the production of superoxide anion and hydrogen peroxide by neutrophils. 相似文献
15.
Biochemistry of the induction and prevention of lipoperoxidative damage in human spermatozoa 总被引:8,自引:1,他引:7
Lipid peroxidation occurs in human sperm cells with damage to the cell
plasma membrane, leading to loss of cytosolic components and hence to cell
'death'. The peroxidation may be induced at high rates in the presence of
Fe2+ and ascorbate. It occurs at slower rates under physiological
conditions as spontaneous lipid peroxidation, which has the following
characteristics. The rate is constant over the time required for complete
loss of motility in the cells of the sperm sample; one can thus use the
time to complete loss of motility (TLM) as a ready measure of the rate.
Loss of motility occurs at a characteristic extent of lipid peroxidation,
assayed in terms of production of the peroxidative breakdown product,
malonaldehyde (MA), that is independent of peroxidation rate. For human
sperm, this extent corresponds to 0.1 nmol MA/10(8) cells. Human
spermatozoa possess the anti-lipoperoxidative defence enzymes, superoxide
dismutase (SOD) and glutathione peroxidase plus glutathione reductase
(GPX/GRD). The SOD activity is highly variable between human sperm samples
while the activities of GPX and GRD are rather more constant. The rates of
production of superoxide anion, O2-, and hydrogen peroxide, H2O2, from
human spermatozoa are variable, but their sum calculated in O2- equivalents
as O2- + 2H2O2 is quite constant. The variability arises from the
variability in SOD activity: all H2O2 produced is from O2- due to the
action of SOD. The essential role of SOD as defence enzyme is inferred from
the observation that TLM of a given sperm sample is directly proportional
to the SOD activity of that sample. The essential role of GPX/GRD is
inferred from the observation that inhibition of GPX, either with
mercaptosuccinate or with complete oxidation of intracellular reduced
glutathione, results in a 20-fold increase in peroxidation rate. The
capacity of the GPX/GRD system appears to be limited by the
glucose-6-phosphate dehydrogenase-catalysed rate of production of NADPH,
the required reductive substrate for GRD. Human spermatozoa appear to have
enough anti-lipoperoxidative defensive capacity for lifetimes long enough
for fertilization but still short enough for ready removal from the female
reproductive tract in good time. Too low a defence capacity could lead to
male infertility.
相似文献
16.
H Gyllenhammar 《Journal of immunological methods》1987,97(2):209-213
Lucigenin-amplified chemiluminescence (LUCL) was induced by .O2- (from the xanthine/xanthine-oxidase reaction) but not, as with luminol-augmented CL (LCL), by myeloperoxidase (MPO) and only weakly by H2O2 or the H2O2-MPO-Cl- system. Neutrophil LUCL induced by fMet-Leu-Phe (fMLP) was dose-dependently inhibited by scavengers of .O2- but not by NaN3, catalase, mannitol or taurine. Response patterns of several soluble stimuli (leukotriene B4 (LTB4), platelet-activating factor (PAF), fMLP, A23187 and phorbol-myristate-acetate (PMA)) were assessed with LUCL. PMA-induced LUCL was protracted, A23187 showed intermediary kinetics whereas fMLP and PAF both showed rapid peak responses at 30-50 s. However, LTB4 was the most rapid initiator of LUCL (7-12 s). The kinetics of fMLP- or PMA-induced neutrophil .O2- production, assessed with the cytochrome C reduction method, correlated well with LUCL. Thus it is suggested that LUCL provides a specific method for studying the kinetic properties of neutrophil .O2- production where stimulus-specific response patterns can be distinguished. 相似文献
17.
Muscle vasodilatation evoked by systemic hypoxia is adenosine mediated and nitric oxide (NO) dependent: recent evidence suggests the increased binding of NO at complex IV of endothelial mitochondria when O(2) level falls leads to adenosine release. In this study on anaesthetised rats, the increase in femoral vascular conductance (FVC) evoked by systemic hypoxia (breathing 8 % O(2) for 5 min) was reduced by oxypurinol which inhibits xanthine oxidase (XO): XO generates O(2)(-) from hypoxanthine, a metabolite of adenosine. By contrast, infusion of superoxide dismutase (SOD), which dismutes O(2)(-) to hydrogen peroxide (H(2)O(2)), potentiated the hypoxia-evoked increase in FVC. However, NO synthesis inhibition reduced the hypoxia-evoked increase in FVC and it was not further altered by SOD. In other studies, the spinotrapezius muscle was pre-loaded with hydroethidine (HE), or dihydrorhodamine (DHR) which fluoresce in the presence of O(2)(-) and H(2)O(2), respectively. In muscle loaded with HE, systemic hypoxia increased fluorescence in endothelial cells of arterioles, whereas in muscle loaded with DHR, fluorescence was diffusely located in and around arteriolar endothelium. We propose that in systemic hypoxia, O(2)(-) generated by the XO degradation pathway from adenosine released by endothelial cells, and released by endothelial mitochondria by increased binding of NO to complex IV, is dismuted to H(2)O(2), which facilitates hypoxia-induced dilatation. 相似文献
18.
Anti-neutrophil cytoplasm autoantibodies (ANCA) directed against proteinase-3 and myeloperoxidase (MPO) activate tumor necrosis factor-alpha-primed neutrophils in vitro. We used neutrophils from one completely and one partially MPO-deficient donor to assess the requirement of MPO expression for neutrophil activation by anti-MPO antibodies. The MPO deficiencies were defined enzymatically, by immunocytochemistry and by immunoblotting. The mutations in the MPO genes of these donors were identified as a combination of a novel splice-site mutation at the 3' end of intron 11 (A-2-->C), a deletion of 14 nucleotides in exon 9 (A1555-C1568), and a novel C1907 --> T (636Thr-->Met) substitution in exon 11 in the completely MPO-deficient donor and as the same splice-site mutation and a novel C995 --> T (332Ala-->Val) substitution in exon 7 in the partially MPO-deficient donor. Monoclonal antibody 4.15 against MPO and MPO-ANCA-immunoglobulin G induced no superoxide anion production in these MPO-deficient neutrophils despite a normal production induced by other stimuli. Thus, the presence of MPO is a conditio sine qua non for neutrophil activation by anti-MPO antibodies. Moreover, we demonstrated that by means of these MPO-deficient cells, hydrogen peroxide may diffuse from neutrophils to surrounding cells, which may contribute to the damage induced by oxygen radicals in the pathology of systemic vasculitides. 相似文献
19.
John A. Kazmierowski John E. Ross David S. Peizner Kirk D. Wuepper 《Journal of clinical immunology》1984,4(1):55-64
The effects of sulfones and sulfonamides on neutrophil myeloperoxidase-mediated iodination and cytotoxicity were studied usingin vitro assays to measure these parameters. Leukocyte iodination was documented using a quantitative assay to measure the iodination of protein by human neutrophils undergoing phagocytosis. Cytotoxicity for the tumor cell line LSTRA by human neutrophils activated by exposure to phorbol myristate acetate was measured by a51Cr release assay. Dapsone, diasone, and sulfapyridine, at concentrations comparable to serum levels obtained by therapeutic doses of drug, effectively inhibited iodination and cytotoxicity mediated by human neutrophils. Other sulfonamides showed little inhibition of either iodination or cytotoxicity. The amount of inhibition was comparable to that seen with the inhibitors azide or cyanide and occurred in a dose dependent manner with all three drugs. A cell-free cytotoxic system using myeloperoxidase, iodide, a H2O2 generating system, and target cells also showed inhibition by dapsone, diasone and sulfapyridine in a similar fashion. The active drugs inhibited both the intra- and the extracellular myeloperoxidase-H2O2-halide cytotoxic systems. Serial iodination studies of four dermatitis herpetiformis patients, evaluated while taking dapsone or sulfapyridine, showed inhibition of iodination by either drug. Levels of IgA immune complexes, as measured by the Raji cell radioimmune assay adapted for IgA, did not change when medication was withheld. These studies demonstrate that dapsone, diasone, and sulfapyridine inhibit both neutrophil iodination and cytotoxicity for tumor cells, while other sulfonamides have no effect. This confirms previous studies showing inhibition by myeloperoxidase mediated iodination by dapsone. Furthermore, the effect on neutrophils is quickly reversible;in vivo administered drug has no effect onin vitro function. The active drugs inhibit both intra- and extracellular cytotoxic systems. This may represent an important mechanism by which these drugs produce their therapeutic effects when used to treat inflammatory skin diseases. 相似文献
20.
Jennie Karlsson Johan Bylund Charlotta Movitz Lena Björkman Huamei Forsman Claes Dahlgren 《Journal of immunological methods》2010,352(1-2):45-53
Neutrophil accumulation at an inflammatory site or an infected tissue is dependent on the recognition of chemotactic peptides that bind to G-protein coupled receptors (GPCRs) exposed on the surface of the inflammatory cells. A GPCR activated by a chemoattractant quickly becomes refractory to further stimulation by ligands using the same receptor. This desensitization phenomenon has been used frequently to characterize new receptor agonists and to determine receptor hierarchies. In this study we show that desensitization patterns differ depending on what read out systems are used to follow neutrophil activity. When monitoring release of superoxide, neutrophils were readily desensitized against repeated stimulations with the prototypical agonist formylmethionyl-leucyl-phenylalanine (fMLF). In contrast, neutrophils were not desensitized for fMLF when cell activity was determined by intracellular calcium ([Ca2+]i). The difference observed was dependent on inactivation of the agonist in one read out system but not in the other, and we suggest several different solutions to the problem. Agonist inactivation occurs through a myeloperoxidase (MPO)/hydrogen peroxide catalyzed reaction, and the problem could be avoided by using a FACS based technique to measure the change in [Ca2+]i, by the use of an agonist insensitive to the MPO/hydrogen peroxide-system or, by adding an MPO inhibitor or a scavenger that removes either superoxide/hydrogen peroxide or the MPO-derived metabolites. 相似文献