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J Lefort

Publications and source records attributed to J Lefort.

At least 73 records · Page 4Linked to original sources
PubMed1987

Interference of the PAF-acether antagonist BN 52021 with passive anaphylaxis in the guinea-pig.

PAF-acether may be involved in anaphylaxis and asthma. We tested the new PAF-acether antagonist BN 52021 against the effects of antigen in passively sensitized guinea-pigs. Bronchoconstriction by ovalbumin administered i.v. (1 mg/kg) or by aerosol (1 or 10 mg/ml for a period of 1 min) was significantly reduced by BN 52021 (1-10 mg/kg), which did not inhibit drop of leukocyte counts after the i.v. challenge. In both cases, when the guinea-pigs were pretreated by propranolol, high amounts of BN 52021 became ineffective against shock. The reduction of the anaphylactic bronchoconstriction, induced by the combination of mepyramine, aspirin and FPL 55712 was not improved by BN 52021. Tested on isolated lung strips from passively sensitized guinea-pig, BN 52021, at a concentration which inhibits PAF-induced contraction (0.1 mM), did not inhibit the anaphylactic contraction triggered by the administration of ovalbumin (10 micrograms/ml) nor the accompanying release of histamine and thromboxane. In contrast, BN 52021 (30 microM) significantly reduced the anaphylactic release of histamine and of thromboxane from perfused lungs of passively sensitized guinea-pigs. The results with the isolated lung strips and the propranolol-treated guinea-pigs in vivo suggest a dissociation between the anti-anaphylactic and the anti-PAF-acether properties of BN 52021.

Airway Resistance↗
PubMed1987

Blockade by methylation inhibitors of the anaphylactic response of guinea-pig lung strips.

1. The combination of two methylation inhibitors 3-deazaadenosine (10(-4) or 4 x 10(-4) M) plus L-homocysteine (2 x 10(-4) M) caused a time-dependent inhibition of antigen-induced contraction, formation of thromboxane B2 (TxB2) and release of histamine from lung parenchyma strips taken from guinea-pigs actively sensitized with ovalbumin (OA). 2. The methylation inhibitors also prevented the lung strip contractions induced by the mediators platelet-activating factor (Paf-acether, 10(-6) M), leukotriene D4 (LTD4, 10(-8) and 3 x 10(-8) M), and in part to arachidonic acid (10(-6) and 10(-5) M), under conditions where the contractions to histamine (10(-6)-10(-4) M) were virtually unaffected. 3. TxB2 formation induced by these mediators or by OA was more affected by the methylation inhibitors than the lung strip contractions, indicating that prostaglandin formation is more sensitive to these inhibitors than the myotropic activity. In contrast, the suppressive effect of the methylation inhibitors on histamine secretion by parenchyma lung strips induced by OA followed the inhibition of the contraction. 4. These results show that inhibitors of methyltransferases interfere with the myotropic responses and with the release of mediators by actively sensitized guinea-pig lung strips stimulated with antigen, and suggest a major role for a methylation process in mediating the contraction of and mediator release by the lung parenchyma.

Adenosine↗
PubMed1987

Interactions between granulocytes and platelets with the guinea-pig lung in passive anaphylactic shock. Correlations with PAF-acether-induced lesion.

To compare the bronchopulmonary effects of anaphylactic shock with those of platelet-activating factor (PAF-acether), antigen (ovalbumin) was administered intravenously to passively sensitized guinea-pig. Subsequent lung alterations were assessed histologically. Within 1 min following ovalbumin, bronchial and arterial constrictions were observed, accompanied by platelet thrombi in the pulmonary microcirculation, intravascular leucocyte accumulation with diapedesis, disruption of endothelium and alterations of type II pneumocytes. Free eosinophilic granules were scattered in the bronchial submucosa. One h after the infusion of ovalbumin, platelet aggregates had disappeared, bronchoconstriction was over, and denudation of the bronchial epithelium was observed. These alterations resemble to those induced by intravenous PAF-acether, which led us to compare the effects of inhaled PAF-acether and antigen at bronchoconstrictor concentrations. In both cases, leucocytes were aggregated in the microcirculation within 2 min and persisted 1 h later. Massive infiltration of eosinophils and activation and clumping of alveolar macrophages were also noted. Our findings support the involvement of PAF-acether in acute anaphylaxis in the guinea-pig.

Anaphylaxis↗
PubMed1987

Effects of sulfinpyrazone and its metabolite G25671 on platelet activation and desensitization and on bronchoconstriction induced by the prostaglandin endoperoxide analog U46619.

Sulfinpyrazone (100 microM) and its thioether metabolite G25671 (50 microM) suppressed arachidonic acid-induced platelet aggregation, thromboxane (Tx) B2 formation and ATP release. Platelet activation by the endoperoxide analog U46619 also was prevented by sulfinpyrazone or G25671 (0.3-1 mM). Previous studies have shown that human platelets pre-exposed to arachidonic acid or to U46619 and then washed and resuspended failed to respond to a second challenge by both arachidonic acid and U46619; desensitization by arachidonic acid and U46619 occurred at a site sensitive to endoperoxides/Tx receptor antagonists; and the desensitizing effects of U46619 were direct, whereas those of arachidonic acid were mediated by a cyclooxygenase-dependent metabolite. We now demonstrate that the presence of sulfinpyrazone or G25671 during platelet exposure to arachidonic acid or U46619 prevented desensitization. We also studied the threshold aggregating concentration of arachidonic acid and U46619 in healthy subjects before and after treatment with sulfinpyrazone and we found a good correlation between ex vivo and in vitro findings. We finally examined the actions of sulfinpyrazone and G25671 on the bronchoconstriction in vivo and parenchymal lung strip contraction in vitro induced by U46619. Neither drug had any preventive effect. Our results demonstrate that sulfinpyrazone and its metabolite G25671 are not only cyclooxygenase inhibitors but can also act as endoperoxide/Tx antagonists and indicate clearly that antagonism of U46619 by both drugs is selective for platelets.

Arachidonic Acid↗
PubMed1986

Effects of PAF-acether and structural analogues on platelet activation and bronchoconstriction in guinea-pigs.

PAF-acether (platelet-activating factor) (1-O-alkyl-2-acetyl-sn-glycerol-3-phosphorylcholine) induces platelet-dependent bronchoconstriction in the guinea-pig which correlates with its in vivo thrombocytopenic effect. We investigated the influence of modifications of the polar head group in position 3 of the glycerol skeleton of PAF-acether on guinea-pig platelet activation and bronchoconstriction. PAF-acether itself induced concentration-dependent platelet activation (EC50 for aggregation = 0.41 nM and EC20 for secretion of ATP = 0.56 nM). The 3-phosphoryl-N-methyl-morpholino ethanol analogue was slightly more active than PAF-acether and the 3-phosphoryl-N-methyl-piperidinium ethanol, 3-phopshoryl-(N-methyl-piperidino-3') methanol and 3-phosphoryl-(N-methyl-hydroxy-4') piperidine analogues were equieffective to PAF-acether in activating platelets. The 3-phosphoryl-piperidino ethanol analogue was 8 times less active than PAF-acether; the 3-phosphoryl-morpholino ethanol analogue and the 1-O-octadecyl-2-O-acetyl-3-O-[trimethyl-ammonio)-propyl) glycerol were inactive up to 1 microM. Our data show that the choline head group is not a compulsory requirement for activity. When injected i.v. to the propranolol-treated guinea-pigs, the platelet-activating analogues also induced bronchoconstriction. Two PAF-acether antagonists, compounds 48740 RP and BN 52021, inhibited PAF-acether-induced platelet activation when added to PRP at the final concentration of 0.1 mM (aggregation inhibited by 91 +/- 4 and by 94 +/- 3% respect.; secretion inhibited by 80 +/- 12 and 79 +/- 10% respectively, mean +/- S.E.M., n = 4). Both antagonists also suppressed platelet activation and in vivo bronchoconstriction, thrombocytopenia, leukopenia and hypotension induced by PAF-acether and the various analogues. Our results indicate that PAF-acether and the analogues studied trigger platelet activation and the consequent bronchoconstriction through mechanisms which share sensitivity to same antagonists.

Adenosine Triphosphate↗
PubMed1986

Interference of BN 52021 (ginkgolide B) with the bronchopulmonary effects of PAF-acether in the guinea-pig.

The interaction between the ginkgolide BN 52021 and the effects of PAF-acether on the bronchopulmonary system of the guinea-pig was studied. In pentobarbitone or ethyl carbamate-anaesthetized animals, BN 52021 (1 mg/kg i.v. or 10 mg/kg p.o.) inhibited bronchoconstriction, the hematocrit increase and the accompanying thrombopenia and leukopenia induced by PAF-acether (33-100 ng/kg) and failed to block the bronchoconstriction produced by collagen, arachidonic acid and the tripeptide formyl-Met-Leu-Phe (FMLP). BN 52021, 3 mg/kg, reduced the bronchoconstriction induced by aerosolized PAF-acether. BN 52021, 300 microM, also inhibited the superoxide production by PAF-acether-stimulated alveolar macrophages and failed to reduce the same effects when triggered by FMLP (0.01-1 microM). BN 52021 blocked the formation of thromboxane-triggered by PAF-acether (100 ng) injected into perfused lung, under conditions where the effects of arachidonic acid where not modified. Finally, pretreatment of parenchyma lung strips with BN 52021 (100 microM) partially inhibited the contraction induced by PAF-acether (0.1 microM) and suppressed the accompanying release of thromboxane. BN 52021 is a selective antagonist of the effects of PAF-acether on the bronchopulmonary system and on circulating blood cells of the guinea-pig.

Animals↗
PubMed1986

Pharmacological modulation of the respiratory and haematological changes accompanying active anaphylaxis in the guinea-pig.

The intrathoracic accumulation of radiolabelled platelets was recorded in anaesthesized, sensitized guinea-pigs concomitantly with changes in airways resistance during active anaphylaxis. Antigen challenge induced an increased airway resistance associated with intrathoracic platelet accumulation, thrombocytopenia and leukopenia. Bronchoconstriction, but not the haematological changes, was modified by a combination of mepyramine, methysergide and aspirin. The addition of FPL 55712 and PGI2 to this cocktail of drugs additionally inhibited the thrombocytopenia and leukopenia but not the intrathoracic accumulation of platelets induced by antigen challenge. PGI2 was alone able to significantly inhibit the intrathoracic platelet accumulation, but not the bronchoconstriction induced by antigen challenge. These results suggest that active anaphylaxis is associated with activation of blood elements and subsequent pulmonary entrapment of platelets but that the platelet release reaction rather than the embolisation of platelet aggregates is the critical step in the induction of allergic bronchoconstriction in the guinea-pig.

Airway Resistance↗
PubMed1986

Pharmacological control of the in vivo passive anaphylactic shock by the PAF-acether antagonist compound BN 52021.

BN 52021 antagonized PAF-acether-induced bronchoconstriction (BC) in the guinea-pig and inhibited BC triggered by antigen in passively sensitized animals. The anti-anaphylactic activity was prevented by propranolol and may either result from an additional property of the drug, independent from PAF antagonism or from different PAF-dependent mechanisms with different responsiveness to the various antagonists.

Anaphylaxis↗
PubMed1986

Interference of the PAF-acether antagonist BN 52021 with endotoxin-induced hypotension in the guinea-pig.

Because of the potential role of PAF-acether in the pathogenesis of endotoxin shock, we examined the preventive and curative effects of BN 52021, a new PAF-acether antagonist in guinea-pig challenged with S. Typhimurium endotoxin. A biphasic reduction of mean arterial pressure was elicited by i.v. endotoxin (300 micrograms/kg) in control animals, with a rapid drop of blood pressure (maximal decrease within 10 min), partial recovery at 20 min and a second gradual decrease after 30 min. Treatment with BN 52021 injected 15 min prior to endotoxin reduced the initial rapid drop of blood pressure from 38.5 +/- 5 mmHg in vehicle-treated controls (n = 15) to 17 +/- 3 mmHg (p less than 0.01) in animals treated with 1 mg/kg BN 52021(n = 10) and to 9.5 +/- 8 mmHg (p less than 0.01) in guinea-pigs treated with 6 mg/kg BN 52021 (n = 5). The early hypotensive phase was associated with severe thrombocytopenia-leukopenia; only the thrombocytopenia was reduced by BN 52021. The prolonged secondary phase of hypotension was reduced by BN 52021 pretreatment whereas a small increase of hematocrit persisted. The two phases of the arterial pressure profile during endotoxic shock were not observed in animals previously made thrombopenic by rabbit and anti-platelet serum and only the late hypotensive phase persisted. This late hypotension induced by endotoxin in thrombopenic animals was suppressed by BN 52021 pretreatment suggesting that BN 52021 may act via a platelet-independent mechanism. The intravenous injection of BN 52021 during the prolonged secondary phase of shock was followed by an immediate increase of the depressed blood pressure. This increase of blood pressure was dose-dependent, maximum at 6 mg/kg BN 52021, and observed in normal and thrombopenic animals. The interference of BN 52021 with endotoxin shock may be related to its PAF-acether antagonist properties and suggests that PAF-acether is an important participant in endotoxic shock.

Animals↗
PubMed1986

A study with BN 52021 demonstrates the involvement of PAF-acether in IgE-dependent anaphylactic bronchoconstriction.

The involvement of platelet activating factor (PAF) in anaphylaxis was examined by recording the pulmonary responses of anesthetized passively sensitized guinea-pigs to the aerosolization of ovalbumin. Animals were tested with and without BN 52021 (a ginkgolide B, PAF receptor antagonist) pretreatment. Aerosolization of ovalbumin produced a bronchoconstriction (BC) which could be made refractory to additional challenges with the antigen. In animals desensitized to ovalbumin, aerosolization of PAF produced an unattenuated BC. Guinea pigs desensitized by repeated aerosolizations of PAF subsequently showed reduced responses to aerosolized antigen suggesting that PAF may be involved in the BC. Animals pretreated with BN 52021, were protected against the effects of systemically administered PAF and also showed reduced responses to aerosolized antigen. Aerosolization of the leukotriene antagonist, FPL 55712, was ineffective against anaphylactic BC under conditions where catecholamine and histamine release were blocked.

Aerosols↗
PubMed1986

Failure of a combined anti-histamine and anti-leukotriene treatment to suppress passive anaphylaxis in the guinea-pig.

Ovalbumin was used to trigger passive systemic anaphylactic shock in guinea-pigs treated with serum provided by actively sensitized animals. Shock was characterized by bronchoconstriction and hypotension, accompanied by leukopenia and moderate thrombocytopenia. Neither aspirin, a cyclooxygenase inhibitor, FPL 55712, a peptido-leukotriene antagonist, nor their combination interfered with shock, under conditions where the selective histamine antagonist mepyramine, up to 20 micrograms/kg, suppressed bronchoconstriction. When the animals were treated with the beta-adrenergic antagonist propranolol, mepyramine lost its activity, even if combined with aspirin and FPL 55712. Lungs provided by the sensitized animals secreted histamine and formed thromboxane A2 when challenged with ovalbumin, but failed to do so when the lungs were collected after systemic shock; demonstrating that in vivo desensitization involves direct effects on the lungs. Parenchyma lung strips from the sensitized animals and lung strips and trachea from non-sensitized animals placed together in an organ bath contracted when exposed to the antigen in presence of mepyramine. The contraction of the sensitized strips was not affected by FPL 55712 nor by the lipoxygenase inhibitors nordihydroguarietic acid and BW755c, but the responses of the non-sensitized tissues were suppressed, demonstrating that, apart from peptido-leukotrienes, parenchyma lung strips from passively sensitized animals generate a leukotriene and histamine-independent contracting activity. Histamine and peptido-leukotrienes do not account for the totality of passive anaphylactic shock in the guinea-pig.

Anaphylaxis↗
PubMed1986

Pharmacological modulation of the effects of N-formyl-L-methionyl-L-leucyl-L-phenylalanine in guinea-pigs: involvement of the arachidonic acid cascade.

The intravenous administration of the chemotactic and secretagogue peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP; 0.3-30 micrograms kg-1) to the guinea-pig induces bronchoconstriction and dose-dependent leukopenia accompanied by mild thrombocytopenia. No electron microscopic evidence of platelet aggregation in lungs or significant accumulation of 111In-labelled platelets in the thoracic region at the height of bronchoconstriction was noted. Bronchoconstriction and leukopenia induced by FMLP were not affected by prostacyclin, by platelet depletion, by the platelet-activating factor (Paf-acether) antagonist BN 52021 or by the histamine H1-antagonist mepyramine. Bronchoconstriction, but not leukopenia, was inhibited by aspirin, whereas the peptido-leukotriene antagonist compound FPL 55712 and the cyclo-oxygenase lipoxygenase inhibitor indomethacin reduced bronchoconstriction to a limited extent only. The mixed cyclo-oxygenase/lipoxygenase inhibitor compound BW 755C was very effective in blocking bronchoconstriction by the highest dose of FMLP used, but failed to interfere with leukopenia. FMLP-induced dose-dependent contraction of parenchymal lung strips was accompanied by the formation of immuno-reactive thromboxane B2 in amounts markedly less than those formed from exogenous arachidonic acid at concentrations equieffective in inducing contractions. FMLP-induced contractions of the guinea-pig lung strip were not modified by mepyramine nor by FPL 55712. They were reduced by indomethacin and aspirin and an even greater reduction was obtained with aspirin used in combination with FPL 55712. BW 755C suppressed the effects of all the concentrations of FMLP tested, whereas tert-butyloxy-carbonyl-L-methionyl-L-leucyl-L-phenylalanine, a chemical analogue of FMLP, displaced the concentration-response curve to the right, without reducing the maximal contraction obtained. The present results indicate that: (a) bronchoconstriction by FMLP is not due to platelet activation, to cyclo-oxygenase-dependent mechanisms or to peptido-leukotriene formation. The inhibitory effect of aspirin and BW 755C involves a property other than cyclo-oxygenase inhibition, which is not shared by indomethacin. (b) The contractile effects of FMLP on parenchymal lung strips follow an interaction with specific receptor sites, as shown by the effectiveness of tert-butyloxy-carbonyl-L-methionyl-L-leucyl-L-phenylalanine, and involves the combined effects of cyclo-oxygenase and lipoxygenase metabolites.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗