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  • 1
    Electronic Resource
    Electronic Resource
    Stimulation of neutrophil oxidative metabolism by indomethacin (1985)
    Springer
    Inflammation research 16 (1985), S. 336-341 
    Details
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Human neutrophils exposed to indomethacin demonstrate an enhanced capacity for superoxide ion (O 2 − ) generation when stimulated with opsonized zymosan. Enhancement is not seen with indomethacin-treated cells exposed to solube oxidative stimuli. To further investigate this phenomenon, O 2 − generation, chemiluminescence, and phagocytosis were assessed in human neutrophils preincubated with indomethacin. Zymosan-stimulated O 2 − release was increased from 150 to 300% of controls in neutrophils exposed to 400 μg/ml. indomethacin. Enhancement was not reversed by removal of indomethacin from the medium prior to addition of the stimulus and was dose-dependent at drug concentrations of 5 to 400 μ/ml. Neutrophils exposed to methacin alone also generated more O 2 − than control cells, although this increment was not sufficient to account for the degree of enhancement seen when indomethacintreated cells were exposed to zymosan. Neutrophil cehmiluminescence induced by zymosan was also increased by exposure to indomethacin, and at a drug concentration of 400 μg/ml (1.1 mM), enhancement randed from 253 to 333% of controls. As was observed with O 2 − generation, chemiluminescence of neutrophils was increased in the presence of indomethacin alone, although, to a degree far less than was seen when drug-treated cells were stimulated with zymosan. Phagocytosis of radiolabeledS. aureus by neutrophils incubated with indomethacin was increased 13±5% over controls (P〈0.01,n=5), but was unaltered by incubation of cells with the buffer used to solubilize the drug. The modest degree of enhancement of phagocytosis suggests that increased particle uptake is not the sole mechanism of oxidative enhancement. The data are in keeping with the hypothesis that indomethacin has a direct effect on the neutrophil plasma membrane and/or the O 2 − -forming oxidase.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01982869
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  • 2
    Electronic Resource
    Electronic Resource
    Antioxidation theory of non-steroidal anti-inflammatory drugs based upon the inhibition of luminol-enhanced chemiluminescence from the myeloperoxidase reaction (1982)
    Springer
    Inflammation research 12 (1982), S. 371-376 
    Details
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The action of non-steroidal anti-inflammatory drugs (NSAIDS) has been ascribed to their ability to block the reaction of arachidonate with cyclooxygenase/peroxidase, thus inhibiting the cellular production of inflammation mediators such as prostaglandins and leukotrienes. However, this and other polymorphonuclear leukocyte (PMN) peroxidases such as myeloperoxidase (MPO) would still be capable of producing destructive oxidants which contribute to inflammation. Sulindac sulfide (Clinoril® sulfide) has recently been shown to scavenge oxidant products of prostaglandin cyclooxygenase/peroxidase and MPO. The MPO−H2O2−Cl− reaction is a potent antimicrobial/cytotoxic system which produces HOCl, a strong oxidant. MPO itself has the ability to oxidize drugs and cellular components, and may be the main oxidant in PMN defenses. An antioxidant/free radical scavenger action of NSAIDs against the MPO system could be a primary mechanism of their anti-inflammatory effects. Other antioxidant/free radical scavengers have anti-inflammatory effects. MPO activity has previously been quantified using chemiluminescence (CL). In this study, NSAIDs from various classes were tested for their ability to inhibit luminol-enhanced CL from MPO. The most potent NSAIDs against MPO-CL were BW755C, phenylbutazone, indomethacin and sulindac sulfide. Salicylates and arylacetic acid derivatives, such as naproxen, also decreased MPO-CL. These drugs are also effective against CL from PMNs, of which MPO may be a main source. This effect of NSAIDs on MPO suggests that NSAIDs may impair the killing mechanism of the PMN, preventing cell destruction and release of inflammation mediators. PMN MPO appears to be a target for the antioxidant/free radical scavenging effects of NSAIDs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01965406
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  • 3
    Electronic Resource
    Electronic Resource
    Comparison of the effects of antioxidant non-steroidal anti-inflammatory drugs against myeloperoxidase and hypochlorous acid luminol-enhanced chemiluminescence (1982)
    Springer
    Inflammation research 12 (1982), S. 232-238 
    Details
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The interaction of myeloperoxidase (MPO) with H2O2 and Cl− provides a potent antimicrobial/cytotoxic system for polymorphonuclear leukocytes (PMNs). MPO-related cytotoxicity may be associated with the formation of toxic oxidant MPO intermediates, HOCl, or both. MPO itself is able to oxidize drugs and cellular components. Non-steroidal anti-inflammatory drugs (NSAIDs) able to act as antioxidant free radical scavengers have recently been shown to inhibit luminol-enhanced chemiluminescence (CL) which results from the MPO−H2O2−Cl− reaction. CL is a measure of the activity of this reaction. At that time it was not clear whether the source of CL which these NSAIDs affected was HOCl or components of the initial MPO−H2O2−Cl− reaction. A NSAID antioxidant mechanism could affect MPO oxidant intermediates and HOCl. This study compares the effects of antioxidant NSAIDs, methylprednisone and free radical scavengers against MPO-based and NaOCl-based luminol-enhanced CL. Most NSAIDs which affected both MPO and NaOCl-CL appeared to share similar mechanisms, suggesting that MPO oxidant internediates and HOCl are susceptible to NSAID effects. However, most NSAIDs were more effective against MPO-CL. The effect of these NSAIDs against MPO-CL followed the profile of NSAIDs effective in previous studies against PMN-CL. One exception to this was methylprednisone, which has no effect on PMN or MPO-CL, yet inhibited NaOCl-CL. This and other data suggest that MPO and not HOCl-related reactions are a major source of PMN-CL. Less effective NSAIDs affected NaOCl-CL better than MPO-CL. While both HOCl and MPO oxidant intermediates may be affected by NSAIDs, it appears that MPO oxidant intermediates or MPO itself are the primary target for NSAID antioxidant free radical scavenging mechanisms. These antioxidant effects impair the major killing system of the PMN and may be NSAIDs' primary anti-inflammatory mechanism. Although our data suggests the production of superoxide anion and hydroxyl radical from the MPO−H2O2−Cl− reaction, the actual presence or involvement of these free radical species is not confirmed herein.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01965152
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  • 4
    Electronic Resource
    Electronic Resource
    Neutrophil priming mechanisms of sulfolipid-I and n-formyl-methionyl-leucyl-phenylalanine (1994)
    Springer
    Journal of biomedical science 1 (1994), S. 253-262 
    Details
    ISSN: 1423-0127
    Keywords: Mycobacterium tuberculosis ; Intracellular calcium ; NADPH oxidase ; Protein kinase c
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The principal sulfatide of virulentMycobacterium tuberculosis, sulfolipid-I (SL-I), both directly stimulates neutrophil superoxide (O 2 − ) release and, at substimulatory concentrations, primes these cells for markedly enhanced oxidative responsiveness to other stimuli. The present study was undertaken to clarify the priming mechanisms by comparing cellular events following priming doses of SL-I with those following priming with N-formyl-methionyl-leucyl-phenylalanine (FMLP). We compared the involvement of the calcium cation (Ca2+), as well as membrane protein kinase C (PKC) activity and the translocation of NADPH oxidase-cytosolic cofactor effected by priming levels of the two agonists. The investigation led to two important conclusions. First, we clearly demonstrate that priming by both SL-I and FMLP results from activation of cellular processes that are not involved in direct oxidative activation. For example, whereas direct induction of O 2 − generation by FMLP and SL-I required increases in intracellular Ca2+, an increase in intracellular calcium concentration ([Ca2+]i) above basal levels was not required for priming. Second, we identified key differences in the cellular responses to priming doses of SL-I and FMLP. Whereas increased membrane PKC activity caused by priming doses of FMLP was only partially blocked by chelation of intracellular Ca2+, Ca2+ chelation completely inhibited the increase in membrane PKC activity caused by SL-I. NADPH oxidase-cytosolic factor translocation to plasma membranes was completely blocked by pertussis toxin when priming doses of SL-I were used. This guanine-nucleotide-binding protein inhibitor had no effect on FMLP-dependent translocation of the oxidase cofactors. The comparative approach introduced in this report provides a valuable and novel method to discern the complex interactions of various cellular processes that regulate the state of activation of stimulated cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02253310
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  • 5
    Electronic Resource
    Electronic Resource
    Differential inhibition of neutrophil superoxide generation by nonsteroidal antiinflammatory drugs (1984)
    Springer
    Inflammation 8 (1984), S. 209-222 
    Details
    ISSN: 1573-2576
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to further characterize the effects of nonsteroidal antiinflammatory drugs on neutrophil superoxide (O2 −) generation, human neutrophils were incubated in the presence of sulfinpyrazone, phenylbutazone, and indomethacin prior to exposure to a variety of oxidative stimuli. Stimuli used included the chemotactic peptideN-formyl-methionyl-leucyl-phenylalanine (FMLP, 5.0 × 10−7 M), NaF (20 mM), phorbol myristate acetate (PMA, 3.2 × 10−7 M), and opsonized zymosan (250μg/ml). superoxide release induced by FMLP was inhibited by all three drugs with half-maximal inhibition (Ki50) at 2.5, 30, and 120μM for sulfinpyrazone, phenylbutazone, and indomethacin, respectively. This inhibition was not due to drug interference with the assay system since comparable inhibition was not observed in a cell-free O2 −-generating system. The neutrophil's response to NaF was blunted by sulfinpyrazone (K i50=400μM) and phenylbutazone (K i50=65μM), but was unaffected by indomethacin. A similar inhibitory pattern was observed when zymosan was used as the oxidative stimulus. Sulfinpyrazone and phenylbutazone inhibited the response to zymosan (K i50s of 425 and 32μM, respectively), whereas indomethacin augmented it. PMA stimulation evoked O2 − production which was inhibited by phenylbutazone (K i50=350μM) but not by sulfinpyrazone or indomethacin in concentrations up to 1 mM. The results support the hypothesis that the enzyme system responsible for neutrophil O2 − generation can be activated by more than one mechanism. The results also emphasize the need to evaluate pharmacologie modulation of neutrophil responses in light of the stimulus used to evoke the response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00916096
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  • 6
    Electronic Resource
    Electronic Resource
    Thrombin-induced prostacyclin biosynthesis in human endothelium: Role of guanine nucleotide regulatory proteins in stimulus/coupling responses (1990)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Cellular Physiology 142 (1990), S. 186-193 
    Details
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: The regulation of prostacyclin (PGl2) synthesis by cultured human umbilical vein endothelium (HUVEC) was investigated. HUVEC monolayer generation of PGl2 was monitored by RIA of 6-keto PGF1α and dose-dependent increases observed with human α-and γ-thrombins, histamine, or arachidonate. Alpha thrombin (10 nM) produced levels of 6-keto PGF1α approximating responses with 1 μM γ-thrombin, 5μM arachidonate, or 10 μM histamine. Diisopropyl phosphorofluo-ridate-inactivated α-thrombin did not stimulate PGl2 release, demonstrating that catalytic activity was required for thrombin-stimulated PGl2 release. Sodium fluoride (NaF), at concentrations known to activate guanine nucleotide regulatory proteins (G proteins), directly stimulated HUVEC PGl2 synthesis in a dose-dependent and time-dependent manner (20 mM NaF, 4.4 ± 0.5-fold increase at 10 min, 11.9 ± 1.5-fold increase at 30 min). Neither α-thrombin nor NaF-stimulated PGl2 release was dependent upon the availability of extracellular Ca+ +. The hypothesis that G proteins are involved in agonist-stimulated PGl2 synthesis was further supported by studies using digitonin-permeabilized HUVEC monolayers challenged with another G protein activator, guanosine 5′-0-3-thiotrisphosphate (GTP γ S), which effected significant dose-dependent increases in PGl2 synthesis compared with control levels of 6-keto PGFα. In contrast, the G-protein inhibitor GDP β S, (guanosine 5′-0-2-thiodiphosphate), attenuated α-thrombin-mediated prostaglandin generation. Treatment of HUVEC monolayers with pertussis toxin (1 μg/ml) did not inhibit the PGl2 synthesis stimulated by either α-thrombin, NaF, or histamine but catalyzed the ADP ribosylation of a 40 kDa membrane protein which cross-reacted with antisera against a synthetic peptide corresponding to an amino acid sequence common to the α-subunit of other G-proteins. Preincubation of HUVEC microsomal membranes with α-thrombin diminished pertussis toxin-catalyzed ADP ribosylation in a time-dependent manner. These data suggest that thrombin stimulation of PGl2 synthesis by HUVEC monolayers requires the catalytically functional enzyme and further suggests that the thrombin-occupied receptor is coupled to phospholipase activities by a pertussis toxin-insensitive guanine nucleotide regulatory protein in human endothelial cell membranes.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcp.1041420123
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  • 7
    Electronic Resource
    Electronic Resource
    Thrombin receptor activating peptides induce Ca2+ mobilization, barrier dysfunction, prostaglandin synthesis, and platelet-derived growth factor mRNA expression in cultured endothelium (1993)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Cellular Physiology 156 (1993), S. 541-549 
    Details
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Endothelial cell activation by thrombin is a key event in wound healing, Inflammation, and hemostasis. To better define thrombin-endothelial cell interactions we synthesized several peptides of varying length corresponding to the initial 14 amino acid sequence of the cloned human platelet thrombin receptor after cleavage at an arginine41 site (R/SFLLRNPNDKYEPF). Thrombin receptor activating peptides (TRAPs) as short as 5 amino acids induced significant levels of PGl2 synthesis and expression of PDGF mRNA in human endothelium and produced dose-dependent cellular contraction and permeability of confluent human umbilical vein and bovine pulmonary artery endothelial monolayers. To explore whether TRAPs utilized similar signal transducing pathways as α-thrombin to accomplish endothelial cell activation, phospholipase C production of the Ca2+ secretagogue IP3 was measured and detected 10 seconds after either TRAP 7 or α-thrombin. Furthermore, TRAPs ranging from 5-14 residues induced significant dose-dependent incsreases in Fura-2 fluorescence indicative of Ca2+ 1 mobilization. These results indicate that thrombin-mediated proteolytic cleavage of the human and bovine thrombin receptor initiates stimulus/coupling respones such phospholipase C activation, Ca2+ mobilization, and protein kinase C activation. The functional consequence of this cellular activation via the cleaved receptor is enhanced cellular contraction, barrier dysfunction, PGI2 synthesis, and expression of PDGF mRNA. © 1993 Wiley-Liss, Inc.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcp.1041560313
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