Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The profiles of actions of lipoxin A4 (LXA4) and lipoxin B4 (LXB4), two lipoxygenase-derived eicosanoids, were examined with human neutrophils. At nanomolar concentrations, LXA4 and LXB4 each stimulated the release of [1-14C]arachidonic acid from esterified sources in neutrophils. Lipoxin-induced release of [1-14C]arachidonic acid was both dose- and time-dependent and was comparable to that induced by the chemotactic peptide f-met-leu-phe. Time-course studies revealed that lipoxin A4 and lipoxin B4 each induced a biphasic release of [1-14C]arachidonic acid, which was evident within seconds (5-15 sec) in its initial phase and minutes (greater than 30 sec) in the second phase. In contrast, the all-trans isomers of LXA4 and LXB4 did not provoke [1-14C]AA release. Lipoxin-induced release of arachidonic acid was inhibited by prior treatment of the cells with pertussis toxin but not by its beta-oligomers, suggesting the involvement of guaninine nucleotide-binding regulatory proteins in this event. Dual radiolabeling of neutrophil phospholipid classes with [1-14C]arachidonic acid and [3H]palmitic acid showed that phosphatidylcholine was a major source of lipoxin-induced release of [1-14C]arachidonic acid. They also demonstrated that lipoxins rapidly stimulate both formation of phosphatidic acid as well as phospholipid remodeling. Although both LXA4 and LXB4 (10(-8)-10(-6) M) stimulated the release of [1-14C]arachidonic acid, neither compound evoked its oxygenation by either the 5- or 15-lipoxygenase pathways (including the formation of LTB4, 20-COOH-LTB4, 5-HETE, or 15-HETE). LXA4 and LXB4 (10(-7) M) each stimulated the elevation of cytosolic Ca2+ as monitored with Fura 2-loaded cells, albeit to a lesser extent than equimolar concentrations of FMLP. Neither lipoxin altered the binding of [3H]LTB4 to its receptor on neutrophils. In addition, they did not stimulate aggregation or induce adhesion of neutrophils to human endothelial cells. Results indicate that both LXA4 and LXB4 stimulate the rapid remodeling of neutrophil phospholipids to release arachidonic acid without provoking either aggregation or the formation of lipoxygenase-derived products within a similar temporal and dose range. Together they indicate that LXA4 and LXB4 display selective actions with human neutrophils and suggest that these eicosanoids possess unique profiles of action which may regulate neutrophil function during inflammation.
 ...
PMID:Lipoxin A4 and lipoxin B4 stimulate the release but not the oxygenation of arachidonic acid in human neutrophils: dissociation between lipid remodeling and adhesion. 216 50

Incubation of human polymorphonuclear granulocytes, monocytes and platelets with sodium fluoride (NaF) results in a time- and dose-dependent generation of leukotrienes and 12-HETE, respectively. This release was not influenced by pretreatment with pertussis toxin or cholera toxin. The mediators are detectable after a lag phase of about 5-10 min. Inactivation of LTB4 by the neutrophils via omega-oxidation into 20-hydroxy-LTB4 and 20-carboxy-LTB4 is inhibited by NaF. In combination with other cell stimuli, NaF showed modulatory effects, such as an enhanced formation of the leukotrienes when FMLP, opsonized zymosan, PMA, and arachidonic acid were applied as stimuli. Prestimulation of cells with NaF causes an increased [3H]guanylylimidodiphosphate binding to isolated membrane preparations, indicating an enhanced exchange rate for GDP to GTP. Our data demonstrate that a direct activation of GTP-binding proteins results in the generation of the inflammatory mediators and provides evidence for the involvement of the signal-transduction pathway.
 ...
PMID:Effect of sodium fluoride on the generation of lipoxygenase products from human polymorphonuclear granulocytes, mononuclear cells and platelets--indication for the involvement of G proteins. 255 86

Leukotriene B4 induced a biphasic change in the cytoplasmic pH of human neutrophils: an initial rapid acidification followed by an alkalinization. The acidification was slightly reduced by the removal of extracellular Ca2+, but the subsequent alkalinization was not. The leukotriene B4-induced alkalinization was dependent on extracellular Na+ and pH, and was inhibited by amiloride and its more potent analogue, 5-(N,N-hexamethylene)amiloride. These characteristics indicate that the cytoplasmic alkalinization is mediated by the Na+-H+ exchange. Oxidation products of leukotriene B4, 20-hydroxyleukotriene B4, 20-carboxyleukotriene B4, and (5S)-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) also stimulated the Na+-H+ exchange, but higher concentrations were required. Treatment of the cells with pertussis toxin inhibited both phases of the leukotriene B4-induced pHi change, while cholera toxin did not affect the pHi change. The alkalinization induced by leukotriene B4 was inhibited by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), an inhibitor of protein kinase C, but was not inhibited by N-(2-guanidinoethyl)-5-isoquinolinesulfonamide which has a less inhibitory effect on protein kinase C. Acidification was not affected by the drugs. These findings suggest that a GTP-binding protein sensitive to pertussis toxin and protein kinase C are involved in the activation of the Na+-H+ exchange stimulated by leukotriene B4.
 ...
PMID:Cytoplasmic pH change induced by leukotriene B4 in human neutrophils. 283 89

Dual-laser flow cytometry, based on the properties of the DNA-binding dyes Hoechst 33342 and propidium iodide, was used, with light and electron microscopy and DNA fragmentation studies, to define the influence of lipoxygenase-derived eicosanoids on apoptosis of human polymorphonuclear neutrophils (PMN) in vitro. Apoptosis was characterized by progression through an early apoptotic phase characterized by condensation of chromatin and coalescence of nuclear lobes, to a late apoptotic phase characterized by nuclear degradation and evanescence, and secondary necrosis. Prolonged exposure of PMN to leukotriene B4 (LTB4) afforded dose-dependent inhibition of constitutive PMN apoptosis (percentage of normal and apoptotic PMN, respectively, after aging for 18 h: vehicle, 30.5 +/- 2.7% and 61.8 +/- 3.2%; LTB4 10(-7) M, 57.6 +/- 1.2% and 37.6 +/- 1.0%) and apoptosis triggered by the classic peptide chemoattractant FMLP. In contrast, apoptosis was not affected by the LTB4 precursor 5(S)-hydroxyeicosatetraenoic acid (HETE), the omega-oxidation LTB4 metabolites 20-hydroxy-LTB4 and 20-carboxy-LTB4, the cysteinyl leukotriene LTC4, the 15-lipoxygenase product 15(S)-HETE, or the lipoxygenase interaction product lipoxin A4. The anti-apoptotic effect of LTB4 was mimicked by 20,20,20-trifluoro-LTB4, LTB4-dimethylamide, and 14,15-dehydro-LTB4, and was blunted by pertussis toxin and genistein, inhibitors of G alpha i GTP-binding proteins and tyrosine kinases, respectively, but not by staurosporine, 15(S)-HETE, or lipoxin A4. This unique pharmacologic profile suggested that LTB4 attenuated apoptosis through activation of cell surface receptors and signaling events distinct from those involved with PMN trafficking, degranulation, and respiratory bursts.
 ...
PMID:Sequential morphologic events during apoptosis of human neutrophils. Modulation by lipoxygenase-derived eicosanoids. 881 21