Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An agonist-activated phospholipase D/phosphatidic acid phosphohydrolase (PAH) pathway was recently demonstrated in human neutrophils, and evidence suggests that phosphatidic acid (PA) and/or diradylglycerol (DG) generated from this pathway participates in activation of the O2(-)-generating respiratory burst. We have used a series of cationic amphiphilic compounds (sphingosine, propranolol, chlorpromazine, and desipramine) and antibiotics (clindamycin, trimethoprim, and roxithromycin) all of which inhibit the respiratory burst, to investigate the role of the phospholipase D/PAH pathway in neutrophil activation. The phosphatidylcholine (PC) pool in intact cells was first labeled using [3H]-1-O-alkyl-lysoPC; released [3H]-PA and [3H]-DG were then quantified after the addition of either chemo-attractant or PMA. Using either agonist, all compounds showed a dose-dependent inhibition of [3H]-DG generation which correlated with inhibition of O2- generation, but compounds failed to inhibit directly the NADPH oxidase in a cell-free system. For either activator, a plot of the ID50 values for O2- generation vs those for DG generation was linear over four orders of magnitude. In many cases, inhibition of [3H]-DG generation corresponded to an increase in [3H]-PA, implicating PAH as the locus of inhibition. Superoxide generation was inhibited under conditions where PA was either elevated or minimally affected. Neither O2- release nor DG generation showed any selectivity for stereoisomers of propranolol, suggesting that this inhibition does not act via a specific binding site on PAH. No evidence was obtained for an effect of the inhibitors on PA mobility as monitored by electron spin resonance studies of spin-labeled PA in a model membrane system. Data are consistent with an effect of the inhibitors at the level of the interaction of PAH with the membrane and/or its substrate. These data imply that DG produced via the phospholipase D/PAH pathway functions in the activation or maintenance of the respiratory burst.
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PMID:Role of phospholipase D-derived diradylglycerol in the activation of the human neutrophil respiratory burst oxidase. Inhibition by phosphatidic acid phosphohydrolase inhibitors. 132 85

Phagocytosis, the process by which leukocytes recognize and destroy invading pathogens, is essential for host defense. The binding of foreign organisms to phagocytic leukocytes initiates a complex signaling cascade which ultimately results in the entrapment and destruction of the pathogen. The signal transduction pathway mediating phagocytosis is the subject of intense investigation and is known to include protein tyrosine kinases, GTP-binding proteins, protein kinase C (PKC), actin polymerization and membrane movement. A rapidly expanding body of evidence suggests that phospholipases play an integral role in phagocytosis by generating essential second messengers. Here we review the data linking activation of phospholipase A2 (PLA2), phospholipase C (PLC) phospholipase D (PLD), and phosphoinositide 3-OH kinase (PI(3)K) to antibody (IgG)-mediated phagocytosis. Evidence is presented that (1) PLA2-derived arachidonic acid (AA) stimulates NADPH oxidase and membrane redistribution during phagocytosis, (2) the inositol-3,4,5-triphosphate (IP3) and diacylglycerol (DAG) products of PLC activate NADPH oxidase and PKC, and (3) sequential activation of PLD and phosphatidic acid phosphohydrolase may provide an alternative pathway for generation of DAG. Additionally, considerable evidence exists that wortmannin, a PI(3)K inhibitor, depresses phagocytosis. This finding is discussed in the context of the extensive effects PI(3)K products have on endocytosis and exocytosis and the potential role of membrane redistribution in phagocytosis. Finally, a model is presented which integrates data obtained from a variety of phagocytic systems and illustrates potential interactions that may exist between phospholipase-derived second messengers and signaling events required for phagocytosis.
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PMID:Phospholipases and phagocytosis: the role of phospholipid-derived second messengers in phagocytosis. 1022 68

Neutrophils from people with poorly controlled diabetes present a primed phenotype and secrete excessive superoxide. Phospholipase A(2) (PLA(2))-derived arachidonic acid (AA) activates the assembly of NADPH oxidase to generate superoxide anion. There is a gap in the current literature regarding which PLA(2) isoform regulates NADPH oxidase activation. The aim of this study was to identify the PLA(2) isoform involved in the regulation of superoxide generation in neutrophils and investigate if PLA(2) mediates priming in response to pathologic hyperglycemia. Neutrophils were isolated from people with diabetes mellitus and healthy controls, and HL60 neutrophil-like cells were grown in hyperglycemic conditions. Incubating neutrophils with the Ca(2+)-independent PLA(2) (iPLA(2)) inhibitor bromoenol lactone (BEL) completely suppressed fMLP-induced generation of superoxide. The nonspecific actions of BEL on phosphatidic acid phosphohydrolase-1, p47(phox) phosphorylation, and apoptosis were ruled out by specific assays. Small interfering RNA knockdown of iPLA(2) inhibited superoxide generation by neutrophils. Neutrophils from people with poorly controlled diabetes and in vitro incubation of neutrophils with high glucose and the receptor for advanced glycation end products ligand S100B greatly enhanced superoxide generation compared with controls, and this was significantly inhibited by BEL. A modified iPLA(2) assay, Western blotting, and PCR confirmed that there was increased iPLA(2) activity and expression in neutrophils from people with diabetes. AA (10 microM) partly rescued the inhibition of superoxide generation mediated by BEL, confirming that NADPH oxidase activity is, in part, regulated by AA. This study provides evidence for the role of iPLA(2) in enhanced superoxide generation in neutrophils from people with diabetes mellitus and presents an alternate pathway independent of protein kinase C and phosphatidic acid phosphohydrolase-1 hydrolase signaling.
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PMID:Diabetes-induced oxidative stress is mediated by Ca2+-independent phospholipase A2 in neutrophils. 2005 41