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1.
Defects in superoxide and hydrogen peroxide production may be implicated in the high incidence of bacterial infections in patients with acute liver failure (ALF). In the present study, oxygen radical production in patients with ALF due to paracetamol overdose was compared with that of healthy volunteers. Neutrophils from 14 ALF patients were stimulated via the complement receptors using zymosan opsonized with ALF or control serum. Superoxide and hydrogen peroxide production by ALF neutrophils stimulated with zymosan opsonized with ALF serum was significantly reduced compared with the control subjects (P < 0.01). This defect persisted when zymosan opsonized by control serum was used (P < 0.05). Superoxide and hydrogen peroxide production in neutrophils stimulated with formyl-methionyl-leucyl-phenylalanine (fMLP) from a further 18 ALF patients was unaffected compared with control neutrophils. Serum C3 complement levels were significantly reduced in ALF patients compared with control subjects (P < 0.0005). These results demonstrate a neutrophil defect in ALF due to paracetamol overdose, that is complement dependent but independent of serum complement, possibly connected to the complement receptor. 相似文献
2.
We evaluated the effect of 4-(2-benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane hydrochloride) on superoxide production by human neutrophils using an MCLA-dependent chemiluminescence assay. Bifemelane hydrochloride dose-dependently inhibited superoxide production by neutrophils stimulated with phorbol myristate acetate, opsonized zymosan, or N-formyl-methionyl-leucyl-phenylalanine, while it had no effect on superoxide production by a hypoxanthine-xanthine oxidase system. These results indicate that bifemelane hydrochloride does not have a scavenging effect, but has an inhibitory effect on superoxide generation by neutrophils. Although this drug is commonly used for treating chronic cerebral infarction, it may also have a protective effect on acute ischemia/reperfusion injury. 相似文献
3.
A repetitive DNA sequence, Rp-alpha, was isolated from rat-derived Pneumocystis carinii. The genome of rat-derived P. carinii contained 10 to 15 copies of Rp-alpha, which were located on most chromosomes, but no Rp-alpha could be detected in P. carinii derived from either humans or mice. Sequence analysis of two copies of the repeat showed them to be related but distinct. Each of them contained several copies of the 9-base sequence TAACCCTAA, arranged as direct repeats. Oligonucleotides consisting of multimers of this 9mer hybridized to the same set of chromosomes recognized by cloned copies of the Rp-alpha repeat. When used in DNA fingerprinting, the Rp-alpha repeat was capable of distinguishing between different isolates of rat-derived P. carinii. 相似文献
4.
Exposure to sulfur dioxide or sulfite aerosols induce inflammatory reactions in the respiratory tract characterized by an influx of neutrophils into the airways. To determine direct intracellular effects of sulfite on human neutrophils, these cells were evaluated ultrastructurally by electron microscopy and analyzed for their extracellular and intracellular respiratory burst activity after incubation with sulfite (0.01-10 mM) in vitro. The respiratory burst was quantitated by measuring both the extracellular release of superoxide anions (O2-) by superoxide dismutase-inhibitable lucigenin-dependent chemiluminescence (CL) and the intracellular generation of hydrogen peroxide (H2O2) by flow cytometry using the reagent dichlorofluorescein diacetate. The addition of sulfite in concentrations of 0.01-1 mM resulted in sixfold increases in CL of resting neutrophils. Neutrophils stimulated with zymosan, phorbol myristate acetate (PMA), or N-formyl-methionine-leucine-phenylalanine further increased CL when sulfite was added. Higher sulfite concentrations (2-10 mM) decreased CL of resting, zymosan-stimulated, and PMA-stimulated cells. When sulfate was added, no changes in CL of resting and zymosan-stimulated neutrophils were seen, indicating that the effect is specific for sulfite. The intracellular generation of H2O2 in resting and PMA-stimulated neutrophils incubated with sulfite (0.1-2 mM) was increased twofold. These findings suggest that sulfite in low concentrations stimulates neutrophils by activating the respiratory burst to produce O2- and H2O2. Ultrastructural studies confirm the stimulating effect of sulfite on neutrophils with sulfite-treated cells exhibiting increased ruffled surface membranes, degranulation changes, and vesiculation similar to those seen in PMA-stimulated cells. 相似文献
5.
Platelet-activating factor (PAF) is a potent chemoattractant for human eosinophils and neutrophils and causes eosinophil and neutrophil recruitment into animal airways. Since eosinophils and eosinophil cationic proteins are thought to play an important role in the pathophysiology of asthma, we have examined the hypothesis that PAF may also stimulate eosinophil cationic protein (ECP) release from human granulocytes. Granulocytes (93% neutrophils, 3% eosinophils) were isolated from the blood of normal volunteers, using metrizamide density gradients, and stimulated in vitro with PAF, L-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) or opsonized zymosan (OPZ). Superoxide generation was measured colorimetrically, granulocyte degranulation by a fluorimetric assay for elastase, and eosinophil activation by specific radioimmunoassay (RIA) for ECP. Granulocyte chemotaxis was also measured. Whilst both PAF and FMLP were potent chemoattractants for human mixed granulocytes (concentrations producing half the maximal effect (EC50s) ca 10 nM), PAF at concentrations below 10 microM was a poor stimulus to superoxide generation, elastase release or ECP release from the same cell population. In contrast, FMLP was a potent stimulus to both superoxide generation (EC50 48 nM) and ECP (EC50 ca 100 nM) and elastase release (EC50 ca 1 microM). OPZ was a potent stimulus to superoxide generation, but was a poor stimulus to ECP or elastase release. Thus, although PAF is a potent chemoattractant for human granulocytes, our results suggest that it alone may not stimulate their subsequent activation and release of cytotoxic products. 相似文献
6.
Y Ito O Kajkenova RJ Feuers KB Udupa VG Desai J Epstein RW Hart DA Lipschitz 《Canadian Metallurgical Quarterly》1998,53(3):M169-M175
BACKGROUND: As assessed by flow cytometry, the increase in hydrogen peroxide in individual neutrophils from old volunteers was significantly greater than in neutrophils from young volunteers. To explain the discrepancy in previous reports that showed reduced superoxide generation with age and our finding, we measured the kinetics of antioxidative enzymes. METHODS: Neutrophils were obtained from young (ages 21-34) and old (ages over 65) volunteers. The increase in hydrogen peroxide following stimulation with formyl peptide in individual neutrophils was assessed by flow cytometry by using dihydrorhodamine 123. The enzyme kinetics was determined from the best fit curve using Michaelis-Menten equations. RESULTS: Aging was associated with a significant reduction in the Vmax for glutathione peroxidase. The decreased activity was not due to selenium deficiency as the serum and neutrophil concentrations were identical with age. Following activation, a significant increase in the Km was noted in neutrophils from young but not from old volunteers. CONCLUSIONS: These results account for the increased intracellular accumulation of hydrogen peroxide as a function of age in stimulated neutrophils. These results provide evidence in humans of an age-related impairment in antioxidative defense mechanisms that support the free radical theory of aging. 相似文献
7.
R Levy F Schlaeffer A Keynan O Nagauker A Yaari E Sikuler 《Canadian Metallurgical Quarterly》1993,17(5):908-914
Neutrophil function was studied in rats with common bile duct ligation. Superoxide production stimulated by phorbol myristate acetate, opsonized zymosan or formyl-methionyl-leucyl-phenylalanine; phagocytosis; and chemotaxis were significantly greater in neutrophils from rats with common bile duct ligation than in sham-operated control rats. Enhanced neutrophil activity was observed within 12 hr of bile duct ligation; it remained increased during the 15-day study. Preincubation of neutrophils from control rats with sera of rats with common bile duct ligation did not increase superoxide generation. This suggests that the high superoxide production observed in neutrophils of rats with common bile duct ligation was not an immediate effect of the serum. Neutrophils of rats with portal vein ligation exhibited normal activity, indicating that portal systemic shunting per se is not the underlying mechanism for increased activity. The elevated levels of AST and alkaline phosphatase, indicating liver damage, that appeared within 12 hr of bile duct ligation correlated with the increased superoxide generation. 相似文献
8.
The granulocyte-macrophage colony stimulating factor (GM-CSF) is an important in vivo regulator of granulopoiesis and neutrophil functions. It is well-known that the immune response and the transmembrane signalling in immune cells change with aging. We wished to elucidate the effects of GM-CSF in itself and in priming the activities of other inflammatory agents on neutrophils of elderly persons. Neutrophils of 20 healthy elderly (aged 60-90 years) and 20 healthy young (aged 20-25 years) subjects were studied for superoxide anion production, intracellular free calcium mobilization, antibody dependent cellular cytotoxicity (ADCC) and intracellular killing activities. It was found that GM-CSF is unable to prime neutrophils of elderly subjects to the action of FMLP, metenkephalin or opsonized zymosan. By the use of Pertussis toxin and H7 it was demonstrated that a different signal transduction pathway in neutrophils of elderly subjects is activated by GM-CSF or FMLP if compared to that of young subjects. These results suggest that the lack of priming could contribute to the greater susceptibility of the elderly to infections and that the change of the signal transduction mechanism in neutrophils of elderly subjects might partly explain this phenomenon. 相似文献
9.
Associations between ethanol-induced cranial neural crest cell (NCC) damage in mammalian embryos and subsequent malformations as observed in human fetal alcohol syndrome have previously been illustrated. The vulnerability of NCCs to this teratogen may result, at least in part, from their sensitivity to free radical damage. To examine relationships between free radical generation and NCC cytotoxicity, primary culture of mouse NCCs was used. NCC viability was determined in both dose- and time-response studies involving ethanol exposure. After 48 hr of culture, cell viability was significantly diminished at all doses tested (i.e., 50, 100, 150, and 200 mM ethanol). At 100 mM ethanol (a dosage that is teratogenic in vivo and in whole embryo culture), cell viability decreased to approximately 50% of control values over the first 12 hr of culture, and decreased further, to approximately 20% by 48 hr. Using nitroblue tetrazolium as a probe, it was observed that exposure of NCCs to ethanol stimulated the production of superoxide anion radicals. Co-treatment of the ethanol-exposed NCCs with free radical scavengers including 300 units/ml of superoxide dismutase, catalase (500 units/ml), or alpha-tocopherol (300 microM) significantly improved NCC viability. These results suggest that the ethanol-induced NCC injury is mediated, at least in part, through the generation of free radicals. To test this hypothesis further, NCCs were exposed in culture to xanthine/xanthine oxidase. Exogenous free radicals generated by the xanthine/xanthine oxidase system resulted in reduced NCC viability, the severity of which increased in a time and enzyme concentration-related manner. Superoxide dismutase (300 units/ml) and catalase (500 units/ml) significantly reduced the effects of the xanthine/xanthine oxidase-generated free radicals on NCC viability. The similarity between the susceptibility of NCCs to ethanol and their susceptibility to exogenous free radicals in concert with the free radical scavenger-mediated amelioration of ethanol and exogenous free radical-induced NCC death strongly suggest that free radicals play a significant role in ethanol-induced NCC death. 相似文献
10.
In order to fertilize the egg, spermatozoa must go through the capacitation process where they experience Ca2+ uptake, increases in cyclic 3',5' adenosine monophosphate (cAMP) concentrations, superoxide anion production, and protein tyrosine phosphorylation. Although the importance of these processes has been described, the interactions between them, as well as the temporal sequence of these events, remain to be demonstrated. Previous studies from our laboratory have demonstrated that tyrosine phosphorylation of p105 and p81 (p105/81), the two major human sperm phosphotyrosine-containing proteins, was under cAMP and oxygen derivatives regulation. In the present study, we investigated the importance of intra- and extracellular Ca2+, as well as the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and the phosphatase inhibitors calyculin A and okadaic acid, in the production of superoxide anion and p105/81 tyrosine phosphorylation. An increase in p105/81 phosphotyrosine content was observed when spermatozoa were incubated in the absence of extracellular Ca2+ or with the calmodulin antagonist N-(6-aminohexyl)-1-naphthalenesulfonamide. However, the human sperm capacitation inducer FCSu (ultrafiltrate of fetal cord serum) requires the presence of the extracellular Ca2+ to induce capacitation, superoxide anion production, and tyrosine phosphorylation of p105/ 81, whereas free intracellular Ca2+ had no effect on these last two processes. The production of superoxide anion by spermatozoa was stimulated by inhibitors of phosphodiesterases and serine/threonine phosphoprotein phosphatases. The tyrosine phosphatase inhibitor vanadate decreased by 40% the FCSu-stimulated superoxide anion production, although it had no effect when used alone. These results suggest that, during sperm capacitation, Ca2+ induces an elevation in cAMP levels; this cAMP, through undefined serine/threonine protein phosphorylation, stimulates the generation of superoxide anion, which, in turn, causes the increase in p105/81 phosphotyrosine contents. 相似文献
11.
E Róth J Lantos G Temes G Varga M Paróczai E Kárpáti 《Canadian Metallurgical Quarterly》1997,36(1-4):306-309
Oxygen reactive species play a significant role in reperfusion tissue damages. In this study we aimed to investigate the mechanisms of injury regarding changes of neutrophil function. In our experiments the left descending coronary artery (LAD) was ligated in Beagle dogs for 1 hour followed by one hour reperfusion. Animals were divided into two groups: Group I. dogs (n = 10) served as control: Group II. the animals (n = 10) were treated by cardioprotective drug Bisaramil. Peripheral blood samples were taken for neutrophil isolation before operation and subsequent reperfusion (5 min, 1 hour). The stimulated superoxide radical generating capacity of polymorphonuclear leukocytes (PMN) was measured. The lipid peroxidation (MDA), amount of reduced glutathione (GSH) and activity of superoxide dismutase (SOD) were measured in non-ischemic and ischemic parts of left ventricle. There was no significant changes either in control or in treated animals in respect to changes of neutrophil radical production after one hour LAD ligature, however there was a significant discrepancy (p < 0.001) between control and treated animals following a 1 hour reperfusion. The values of MDA in the ischemic-area increased characteristically in the Group I. parallel with decrease of scavenger GSH and SOD. In contrast in Group II., where depleted PMN radical production was observed endogenous scavengers were preserved on a higher level. In summary we can conclude that diminished superoxide radical production of circulating neutrophils during reperfusion has beneficial effects on tissue injury caused especially by free radicals. 相似文献
12.
HJ Majima TD Oberley K Furukawa MP Mattson HC Yen LI Szweda DK St Clair 《Canadian Metallurgical Quarterly》1998,273(14):8217-8224
Alkalosis is a clinical complication resulting from various pathological and physiological conditions. Although it is well established that reducing the cellular proton concentration is lethal, the mechanism leading to cell death is unknown. Mitochondrial respiration generates a proton gradient and superoxide radicals, suggesting a possible link between oxidative stress, mitochondrial integrity, and alkaline-induced cell death. Manganese superoxide dismutase removes superoxide radicals in mitochondria, and thus protects mitochondria from oxidative injury. Cells cultured under alkaline conditions were found to exhibit elevated levels of mitochondrial membrane potential, reactive oxygen species, and calcium which was accompanied by mitochondrial damage, DNA fragmentation, and cell death. Overexpression of manganese superoxide dismutase reduced the levels of intracellular reactive oxygen species and calcium, restored mitochondrial transmembrane potential, and prevented cell death. The results suggest that mitochondria are the primary target for alkaline-induced cell death and that free radical generation is an important and early event conveying cell death signals under alkaline conditions. 相似文献
13.
1. The actions of N-acetylcysteine (NAC) on hydrogen peroxide (H2O2) and leukotriene B4 (LTB4) production by human resting and stimulated peripheral blood neutrophils and alveolar macrophages were investigated. 2. At a concentration of 100 microM, NAC significantly (P < 0.01) suppressed the accumulation of H2O2 in the incubation medium of resting and opsonized zymosan (OZ; 0.5 mg ml[-1])- or N-formylmethionyl-leucyl-phenylalanine (fMLP; 1 microM)-stimulated neutrophils and of resting and OZ-stimulated macrophages. At concentrations of 10 microM and above, NAC augmented significantly the level of LTB4 in the supernatants of OZ- and fMLP-stimulated neutrophils (P < 0.01 and P < 0.05, respectively) and OZ-stimulated macrophages (P < 0.05 at 10 microM, P < 0.01 at 100 microM NAC). 3. NAC (100 microM) caused a significant (P < 0.01) reduction in the quantity of measurable H2O2 when incubated with exogenous H2O2 concentrations equivalent to those released from OZ-stimulated neutrophils and macrophages. At no concentration did NAC affect quantitites of measurable LTB4 when incubated with exogenous LTB4. 4. Superoxide dismutase (SOD), which catalyzes the conversion of superoxide anion to H2O2 had no significant effect on LTB4 production by human neutrophils. In contrast, catalase, which catalyzes the conversion of H2O2 to H2O and O2, caused a pronounced, statistically significant (P < 0.01) increase in the levels of LTB4 measured in the supernatants of OZ- and fMLP-stimulated neutrophils. 5. H2O2 (12.5 microM and 25 microM, concentrations equivalent to those measured in the supernatants of activated neutrophils and alveolar macrophages, respectively) caused a small (13%) decrease in the quantity of measurable LTB4 (P = 0.051 and P < 0.05 at 12.5 microM and 25 microM, respectively) that was inhibited by NAC (100 microM) but not by catalase (400 u ml[-1]). 6. In conclusion, the anti-oxidant drug, NAC, increases LTB4 production by human neutrophils and alveolar macrophages, probably through the elimination of cell-derived H2O2. LTB4 undergoes a H2O2-dependent oxidation that is inhibited by NAC but this is unlikely to account fully for the increased levels of LTB4, suggesting that NAC may increase LTB4 production by blocking the H2O2-dependent inhibition of a synthetic enzyme, such as 5-lipoxygenase. 相似文献
14.
ES Kaneshiro Z Guo D Sul KA Kallam K Jayasimhulu DH Beach 《Canadian Metallurgical Quarterly》1998,39(10):1907-1917
Pneumocystis carinii carinii and rat lung phospholipids contained 3-6% 1-alkyl-2-acyl glycerols composed of the glyceryl ether species, 1-O-octadecyl glycerol (batyl alcohol), 1-O-octadec-9-enyl glycerol (selachyl alcohol), 1-O-hexadecyl glycerol (chimyl alcohol), and 1-O-hexadec-9-enyl glycerol. Of the major phospholipid classes, phosphatidylinositol (PI) and phosphatidylserine contained the highest percentage of alkyl acyl glycerols. Methylprednisolone treatment caused an increase in alkyl acyl PI of rat lung lipids from 12% to 45%. As the PI concentration in lung phospholipids increases in rats treated with methylprednisolone, the increase in alkyl acyl PI was substantial; the proportions of alkyl acyl phosphatidylethanolamine and alkyl acyl lyso phosphatidylcholine (PC) also increased. Pneumocystis phospholipids contained higher proportions of alkyl acyl PC than the phospholipids of the lungs from normal and immunosuppressed uninfected rats. The glyceryl ether compositions of P. carinii carinii PC and lyso PC were similar, which suggests that lyso PC in the organism is derived by phospholipase A2 action on PC. This was not the case for PC and lyso PC of the lung controls. Analysis of the free fatty alcohols, precursors of glyceryl ethers identified only saturated species in P. carinii carinii and rat lung controls. Thus, the introduction of a double bond in the alcohol moiety of glyceryl ethers occurs after formation of the ether linkage between fatty alcohol and the glyceryl backbone. 相似文献
15.
K Mikawa H Akamatsu K Nishina M Shiga N Maekawa H Obara Y Niwa 《Canadian Metallurgical Quarterly》1997,41(4):524-528
BACKGROUND: Reactive oxygen species (ROS) generated from neutrophils accumulated in various major organs are thought to play a pivotal role in the pathogenesis of host auto-injury. Lidocaine has been shown to reduce the injury. We investigated the effect of local anaesthetics (lidocaine, mepivacaine and bupivacaine) on ROS production by neutrophils using an in vitro system. METHODS: We measured the production of superoxide (ferricytochrome c method), hydrogen peroxide (H2O2: scopoletin fluorescence technique), and hydroxyl radical (OH.: ethylene gas method) by neutrophils isolated from human adult volunteers in the absence and presence of lidocaine (2-200 micrograms/mL), mepivacaine (3-300 micrograms/mL), and bupivacaine (3-300 micrograms/mL). We also measured the ROS generation in a cell-free (xanthine-xanthine oxidase) system. RESULTS: Lidocaine and mepivacaine at higher levels significantly decreased the production of ROS by neutrophils. However, these local anaesthetics at clinically relevant blood concentrations had no effect on the levels of ROS. Furthermore, lidocaine and mepivacaine failed to reduce ROS generated by the cell-free system. Bupivacaine did not decrease ROS generation by either generating system. CONCLUSION: In conclusion, in the present in vitro system, only concentrations of lidocaine and mepivacaine 100-fold higher than clinically feasible ones reduced ROS production by human neutrophils. However, the local anaesthetics at clinically relevant blood concentrations had no suppressive effect. Further studies using in vivo systems are required to elucidate the inhibitory effects of local anaesthetics on ROS generation in clinical settings. 相似文献
16.
To investigate the nature of the oxidative event that occurs during phagocytosis of retinal outer segments (ROS) by cultured human retinal pigment epithelial (RPE) cells, cells were incubated with isolated bovine ROS labeled with either the fluorescence probe carboxy-SNAFL-2 or the nonfluorescent, oxidizable probe 2',7'-dichlorodihydrofluorescein (H2DCF). The increase in fluorescence following phagocytosis was measured by a flow cytometer. Other measurements included: oxygen consumption using a Clark-type oxygen electrode, extracellular superoxide release by superoxide dismutase inhibitable lucigenin chemiluminescence, intracellular hydrogen peroxide (H2O2) production, and the effect of catalase inhibition on cellular thiobarbituric acid-reactive substances (TBARS) caused by phagocytosis. The activities of the enzymes NADPH oxidase and palmitoyl-CoA oxidase were also measured. H2DCF attached to bovine ROS was oxidized during phagocytosis with a time course suggesting oxidation subsequent to ROS uptake. Measurements of oxygen consumption showed a time-dependent increase of 10%, 4 h after ROS feeding, attributable to a doubling of the cyanide-resistant oxygen consumption. Intracellular H2O2 production also doubled 4 h after ROS phagocytosis. ROS uptake by RPE cells produced no significant extracellular superoxide, while extracellular superoxide production was readily demonstrated in a control macrophage cell line. Enzyme activity measurements showed that incubation of RPE cells with ROS doubled catalase activity without affecting superoxide dismutase or glutathione peroxidase activities. Inhibition of catalase during ROS uptake increased TBARS by 66%. Other enzyme activity measurements showed that human RPE cells possess both NADPH oxidase and palmitoyl-CoA oxidase activities. We conclude that ROS phagocytosis subjects RPE cells to an oxidative event on the same order of magnitude as measured in a macrophage. The event is not an extracellular macrophage-type respiratory burst and may be due to intracellular H2O2 resulting from an NADPH oxidase in the phagosome or from beta-oxidation of ROS lipids in peroxisomes. Irrespective of case, the enzyme catalase appears to be essential in protecting the RPE cell against reactive oxygen species produced during phagocytosis. 相似文献
17.
Anesthetics and sedatives contribute to postoperative immunosuppression. Interleukin-8 (IL-8) is a chemotactic and activating factor that mediates neutrophil adhesion and margination and is essential for host defense. We investigated the effect of anesthetics on isolated human polymorphonuclear leukocyte production of IL-8. Healthy human polymorphonuclear leukocytes were isolated using a single-step density gradient and stimulated with lipopolysaccharide in the presence of varying concentrations of propofol or midazolam for up to 20 h. IL-8 was measured in both culture supernatants and cell lysates using enzyme immunoassay, and IL-8 mRNA in cells was measured using Northern blotting and phosphorimaging. Data were analyzed using Kruskal-Wallis analysis of variance or the Mann-Whitney U-test as appropriate. Lipopolysaccharide increased extracellular accumulation of interleukin-8, which was suppressed by both propofol (P = 0.025) and midazolam (P = 0.028). However, intracellular IL-8 increased with exposure to lipopolysaccharide (P = 0.028) and remained increased with both anesthetics. Northern blot analysis also revealed increased IL-8 mRNA levels in the presence of both midazolam and propofol, which was confirmed by molecular imaging. These data strongly suggest that the anesthetics modulate transport or secretion of IL-8 protein from the cell. Suppression of IL-8 by anesthetics and sedatives may predispose postoperative and intensive care patients to infection. Implications: Anesthesia causes immune suppression and alters neutrophil function. We investigated the effect of propofol and midazolam on interleukin-8, a neutrophil chemotactic agent in human neutrophils. Both anesthetics decreased extracellular interleukin-8 accumulation, but intracellular levels and mRNA remained high. This suggests that propofol and midazolam alter interleukin-8 secretion from cells. 相似文献
18.
AM Nagy F Vanderbist N Parij P Maes P Fondu J Nève 《Canadian Metallurgical Quarterly》1997,10(5-6):287-292
In lung diseases such as chronic obstructive pulmonary disease (COPD) or cystic fibrosis, the activation of phagocytic cells produces high amounts of cytotoxic reactive oxygen species (ROS) that are partly implicated in the pathogenic process. In this study, the ex vivo antioxidant activity of nacystelyn (NAL), a recently developed mucoactive thiol-containing agent, was investigated using the respiratory burst of human blood polymorphonuclear neutrophils (PMNs). The ROS generation was induced by serum-opsonized zymosan and assessed with luminol- and lucigenin-enhanced chemiluminescence (ECL). The activity of NAL was compared with N-acetylcysteine (ACC) and captopril, other thiol-containing pharmacological agents having documented antioxidant properties. The three drugs significantly inhibited the ECL response of activated PMNs in the presence of luminol, a luminogenic agent which mostly reflects the production of hydroxyl and hypohalite radicals. NAL was more efficient than the other two drugs: the concentrations producing a 50% inhibition (IC50) of total luminol-ECL were 290 microM, 1580 microM and 760 microM for NAL, ACC and captopril, respectively. The inhibition of the lucigenin-ECL response of activated PMNs was less marked for all compounds suggesting a poorer reactivity with superoxide radicals. These findings demonstrate that NAL, at concentrations obtainable in vivo by inhalation, impairs the PMNs chemiluminescence response related to hydroxyl and hypohalite radicals production. As those radicals are highly cytotoxic, NAL appears as a promising agent in the prevention of oxidative lung damage caused by an active inflammatory response. 相似文献
19.
The release of proteolytic enzymes and generation of strong oxidants such as the hydroxyl radical by activated neutrophils has been proposed to play an important role in mediating toxin-induced liver injury. The antithyroid drug propylthiouracil protects against liver injury induced by many hepatotoxic agents and markedly reduces mortality in patients with alcoholic liver disease. However, the mechanism(s) by which propylthiouracil protects against liver injury is not well understood. The present studies investigate the effect of antithyroid drugs on proteolytic enzyme activity and on hydroxyl radical generation from activated neutrophils. In the presence of hydrogen peroxide and chloride, neutrophil myeloperoxidase, an enzyme from the same gene superfamily as thyroid peroxidase, generates hypochlorous acid which inactivates alpha-1-proteinase inhibitor (A1PI) present in serum. This inactivation allows neutrophil-released proteolytic enzymes to attack cells. In the present study myeloperoxidase activity was inhibited fully at therapeutic concentrations by antithyroid drugs (propylthiouracil and methimazole). Antithyroid drugs fully prevented hypochlorous acid formation, and prevented neutrophil-mediated inactivation of A1PI, with concomitant blockage of proteolytic activity. Conversely, generation of both superoxide and hydroxyl radicals by activated neutrophils was unaffected by propylthiouracil. The production of these oxygen radicals was fully inhibited by the NADPH oxidase inhibitor diphenylene iodonium chloride, however. These studies indicate that antithyroid drugs are unlikely to prevent cell injury by inhibiting hydroxyl radical generation or by scavenging hydroxyl radicals, but are likely to exert their hepatoprotective anti-inflammatory action by inhibiting neutrophil myeloperoxidase, an enzyme akin to thyroid peroxidase. 相似文献
20.
MM Hardy AG Flickinger DP Riley RH Weiss US Ryan 《Canadian Metallurgical Quarterly》1994,269(28):18535-18540
In this study, we evaluated the ability of low molecular weight manganese-based superoxide dismutase mimetics to attenuate neutrophil-mediated oxygen radical damage to human aortic endothelial cells in vitro. Human neutrophils, when exposed to tumor necrosis factor-alpha and the complement compound C5a, induced endothelial damage assessed by the release of 51Cr into the medium. This damage correlated with the amount of superoxide generated by neutrophils. Three superoxide dismutase mimetics, with catalytic rate constants for superoxide dismutation ranging from 4 to 9 x 10(7) M-1 S-1, inhibited neutrophil- or xanthine oxidase-mediated endothelial cell injury in a concentration-dependent manner. A similar manganese-based compound with no detectable superoxide dismutase activity was ineffective in inhibiting injury. Fluorescent studies of the neutrophil respiratory burst showed that the superoxide dismutase mimetics were protective without interfering with the generation of superoxide by activated neutrophils. Catalase, elastase inhibitors, and desferrioxamine mesylate (an iron chelator and hydroxyl radical scavenger) were not protective against cell injury. This investigation demonstrates that neutrophil-mediated human aortic endothelial cell injury in vitro is mediated by the superoxide anion and that low molecular weight manganese-based superoxide dismutase mimetics are effective in abrogating this damage. 相似文献