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Biomedical subjects

J Lefort

Publications and source records attributed to J Lefort.

At least 55 records · Page 3Linked to original sources
PubMed1991

Interference of BN 52021, an antagonist of PAF, with different forms of active anaphylaxis in the guinea-pig: importance of the booster injection.

1. BN 52021, an antagonist of platelet activating factor (PAF), was inactive against bronchoconstriction in guinea-pigs sensitized with low amounts of ovalbumin (OA) injected twice, at a 14 day interval and challenged i.v. 7 days later. 2. Serum IgG titers increased for 7 weeks after the booster injection at day 14 and returned to low levels at day 96. 3. Administered by the intratracheal (i.t.) route at 1 mg, BN 52021 failed to inhibit bronchoconstriction induced by the i.t. administration of OA to guinea-pigs tested 7, 28, 56 and 84 days after the booster injection, even when the titers of circulating IgG had declined with time. BN 52021 was also inactive against bronchoconstriction in guinea-pigs boosted at day 98 and tested 7 days later and against contractions and thromboxane (Tx) B2 and histamine release induced by OA-challenged parenchymal lung strips from the boosted guinea-pigs. 4. Sensitized unboosted guinea-pigs displayed reduced IgG serum titers. Used 21 or 70 days after the sensitizing injection, they did develop bronchoconstriction upon the i.t. instillation of OA, which was blocked by BN 52021. The latter also inhibited OA-induced contractions of lung parenchymal strips from these unboosted guinea-pigs. 5. When boosted and non-boosted guinea-pigs received OA i.t. and bronchoalveolar lavage fluid was collected 10 min later, the number of eosinophils increased markedly in boosted, but not in non-boosted guinea-pigs. 6. The booster injection of antigen thus modifies the response of the lung and PAF appears to be relevant for antigen-induced bronchoconstriction in unboosted animals, but loses its major role following the booster injection.

Anaphylaxis↗
PubMed1991

Lipopolysaccharide from Escherichia coli reduces antigen-induced bronchoconstriction in actively sensitized guinea pigs.

Bronchoconstriction (BC) is the main feature of anaphylaxis in the guinea pig. Since LPS induces lung inflammation and antigen-induced BC depends on the endogenous formation of histamine and arachidonate metabolites, we studied whether LPS might modulate antigen-induced BC. Guinea pigs were sensitized subcutaneously with 10 micrograms ovalbumin (OA) on days 0 and 14. LPS (100 micrograms/kg) was injected intravenously on day 21, and daily injections of LPS were continued before the antigenic challenge on day 22, 23, 24, or 25. Intratracheal injection of 100 micrograms OA induced an abrupt and reversible BC. Single or repetitive injections of LPS reduced BC. LPS is likely to reduce the OA-induced BC by affecting the histamine-dependent component of BC, since (a) LPS induced a partial degranulation of lung mast cells; (b) BC is reduced by mepyramine, an histamine receptor antagonist; (c) LPS did not affect BC in mepyramine-treated guinea pigs; (d) LPS reduced histamine release by OA-stimulated guinea pig lungs in vitro. Moreover, the in vitro OA-induced production of arachidonate metabolites was also reduced by LPS. The decreased formation of TXB2 was not only secondary to a reduced release of histamine, since LPS inhibited TXB2 formation in the presence of mepyramine. Finally, the FMLP-induced BC and mediator release were inhibited by LPS, whereas the platelet activating factor-induced pulmonary responses were not. Thus, the protective effect of LPS is not antigen-specific and does not result from a general desensitization. These studies indicate that a single dose of LPS reduces the antigen-induced BC by reducing histamine release from lung mast cells, although a decreased formation of eicosanoids may contribute to the protective effect of LPS.

Animals↗
PubMed1990

An alternative point of view on experimental lung hyperreactivity.

The booster injection of antigen to pre-sensitized guinea-pigs induces lung modifications leading to hyperresponsiveness and to shifts in the profile of the effective drugs. The introduction of the concept of lung inflammation offers new targets for drug discovery.

Animals↗
PubMed1990

The booster injection of antigen during active sensitization of guinea-pig modifies the anti-anaphylactic activity of the PAF antagonist WEB 2086.

1. Serum IgG levels of sensitized guinea-pigs bled at various times after the booster injection were evaluated and its capacity to sensitize passively lung strips from normal guinea-pigs assessed. Following the booster injection, both serum IgG and the ability to sensitize passively lung strips increased during the first week and decreased slowly thereafter. 2. The PAF antagonist WEB 2086 (3 mg kg-1, i.v.) blocked the anaphylactic bronchoconstriction induced by intravenous administration of ovalbumin (1 mg kg-1) when guinea-pigs were challenged 2 and 4 days after the booster injection, but became ineffective when tested in guinea-pigs challenged 7, 28 and 56 days after the booster injection. 3. The ability of WEB 2086 to reduce anaphylactic bronchoconstriction of guinea-pigs challenged 2 and 4 days after the booster injection was unrelated to either the selective involvement of one type of immunoglobulin, low IgG titres in sera or a reduced sensitizing capacity. 4. The booster injection, which accounts for the loss of efficacy of WEB 2086 from the fourth day thereafter, probably operates as a PAF-independent inflammatory challenge. 5. The protocol for immunisation and the day of experiment after the booster injection determines the sensitivity of the anaphylactic bronchoconstriction to inhibition of PAF antagonists.

Anaphylaxis↗
PubMed1990

Protection by nedocromil sodium of active immunization-induced bronchopulmonary alterations in the guinea pig.

The effect of nedocromil sodium on PAF-acether- and antigen-induced bronchoconstriction (BC) and mediator release in lungs from actively sensitized guinea pigs and on the eosinophil content of bronchoalveolar lavage (BAL) was investigated. Guinea pigs were actively sensitized by two subcutaneous injections of 10 micrograms ovalbumin in 1 mg AI(OH)3 at 2-wk intervals. One week after the second (booster) injection, the lungs were removed, perfused in the absence or presence of indomethacin, and challenged at 10-min intervals with PAF-acether (1 and 100 ng) and with ovalbumin (1 micrograms). No inhibition of PAF-acether- and antigen-induced BC or mediator release from sensitized lungs was observed when nedocromil sodium (10 microM) was added directly to the buffer solution. By contrast, when guinea pigs were treated for 1 wk before the experiment with nedocromil sodium (30 mg/kg per day), BC and the release of leukotrienelike material (but not of thromboxane B2) to 1 ng PAF-acether were reduced by around 50% (p less than 0.05) and 62% (p less than 0.05), respectively. No inhibition was observed for 100 ng PAF-acether and 1 micrograms ovalbumin. Furthermore, nedocromil sodium markedly impaired histamine secretion induced by both PAF-acether and antigen administration. Nedocromil sodium did not affect the titers of circulating ovalbumin-specific immunoglobulin G, as detected by an enzyme-linked immunosorbent assay. The 1-wk treatment with nedocromil sodium also reduced markedly the proportion of eosinophils in the BAL of sensitized guinea pigs, whereas it was ineffective when injected once subcutaneously at the dose of 30 mg/kg 2 h before the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Reduced responsiveness of bronchoalveolar cells from sensitised guinea-pigs to the cyclic AMP--stimulating effect of prostaglandin E2 and beta-adrenoceptor agonists.

Prostaglandin E2 and the beta-adrenoceptor agonist salbutamol were less effective in increasing the intracellular cAMP content of bronchoalveolar cells and adherent alveolar macrophages from ovalbumin-sensitised as compared to control guinea-pigs. This refractoriness to the cyclic AMP-stimulating effects of PGE2 and salbutamol induced by the sensitisation procedure may be relevant to the altered bronchopulmonary responsiveness in asthma.

Adrenergic beta-Agonists↗
PubMed1989

Limited interference of specific Paf antagonists with hyper-responsiveness to Paf itself of lungs from actively sensitized guinea-pigs.

1. The interference of various platelet-activating factor (Paf) antagonists with Paf- and antigen-induced effects in isolated lungs from actively sensitized guinea-pigs was investigated. 2. WEB 2086 and BN 52021, two antagonists structurally unrelated to Paf, at concentrations 10-100 fold above those exerting a potent and selective inhibition of the effects of Paf in lungs from non-immunized guinea-pigs, failed to inhibit bronchoconstriction and mediator release evoked by the phospholipid when administered into lungs from actively sensitized animals. 3. In contrast to WEB 2086 and BN 52021, antagonists such as Ro 19-3704 and Ro 19-1400, structurally related to the Paf molecule, at concentrations which abrogate the effects of Paf in lungs from non-immunized guinea-pigs, inhibited bronchoconstriction and release of histamine and leukotriene-like material evoked by the intra-arterial administration of Paf into lungs from actively sensitized animals. 4. Ro 19-3704 and Ro 19-1400 also inhibited markedly the release of leukotriene C4 (LTC4)-like material and, to a smaller extent, the histamine secretion induced by 10 micrograms arachidonic acid. 5. CV 6209, another Paf antagonist structurally related to the phospholipid, failed to antagonize its bronchopulmonary and secretory effects in sensitized lungs. 6. All the antagonists used, irrespective of their ability to interfere or not with bronchoconstriction and mediator release triggered by Paf, suppressed oedema formation as measured by the increase in lung wet weight induced by either Paf or ovalbumin. 7. Our results indicate that: (i) the increase in vascular permeability and the subsequent oedema formation on one hand and the bronchopulmonary effects of Paf on the other hand are mediated by different mechanisms; and (ii) active sensitization provokes a marked modification of the lung reactivity to Paf.

Animals↗
PubMed1989

Alveolar macrophages and eicosanoids but not neutrophils, mediate bronchoconstriction induced by FMLP in the guinea-pig.

1. N-formyl-methionyl-leucyl-phenylalanine (FMLP), when administered by aerosol to guinea-pigs, induced a dose-dependent bronchoconstriction (BC) with no overt effect on platelet and leukocyte blood counts. Repeated administration of FMLP by aerosol was followed by desensitization. 2. Electron microscopy studies showed that administration of FMLP by aerosol is accompanied by alveolar macrophage activation, accumulation and aggregation in the alveolar lumens. Non-degranulated eosinophils were observed in the lungs and a few platelet micro-aggregates in the pulmonary microvasculature. 3. No significant accumulation of 131I-labelled albumin, 111In-labelled neutrophils or 111Inlabelled platelets was detected in the lungs after the administration of FMLP by aerosol, whereas the intravenous administration was accompanied by an increase of extravascular albumin and significant neutrophil sequestration in the lungs. 4. Aspirin administered intravenously or by aerosol reduced significantly the BC induced by an aerosol of FMLP. By contrast, intravenous indomethacin reduced only BC induced by the sub-maximal dose of FMLP as an aerosol whereas, when administered by inhalation, it inhibited BC induced by FMLP administered either intravenously or by aerosol at all the concentrations tested. 5. FMLP induced a dose-dependent contraction of the guinea-pig trachea, which was not inhibited by indomethacin. 6. The dual cyclo-oxygenase/lipoxygenase inhibitor compound BW755C suppressed the BC induced by an aerosol of FMLP at all the concentrations used, whereas the histamine H1-antagonist mepyramine was inactive. 7. Leukocyte depletion with vinblastine failed to reduce BC induced by intravenous or an aerosol of FMLP. 8. Our studies indicate that: (a) FMLP administered by aerosol induces dose-dependent BC followed by desensitization, indicating that local mechanisms account for BC; (b) BC induced by i.v. FMLP, but not by its inhalation, is accompanied by albumin extravasation and neutrophil sequestration in the lungs; (c) BC by either i.v. or an aerosol of FMLP is not due to neutrophil activation; (d) inhalation of FMLP induces BC accompanied by accumulation of activated alveolar macrophages, non-degranulated eosinophils and a few platelet microaggregates in the lung; (e) both cyclo-oxygenase and lipoxygenase metabolites are involved in the BC induced by an aerosol of FMLP.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1989

PAF-acether and experimental anaphylaxis as a model for asthma.

Several lines of evidence indicate that platelet-activating factor (PAF-acether) is implicated in hypersensitivity reactions. Indeed, PAF-acether reproduces the features of asthma in vivo and in vitro, since it induces bronchoconstriction, hypotension, and hemoconcentration and activates platelets and leukocytes. Both PAF-acether and antigen evoke eosinophil margination and diapedesis in guinea pig lung parenchyma and bronchial submucosa. Furthermore, intradermal administration of PAF-acether to atopics induces a more intense eosinophil degranulation as compared to normal subjects. PAF-acether also induces bronchopulmonary hyperresponsiveness in various animal models and in humans. We showed that lungs from actively sensitized guinea pigs exhibit an in vitro bronchopulmonary hyperresponsiveness to PAF-acether as compared to nonsensitized animals. This phenomenon is probably due to a lung invasion by inflammatory cells or to a variation of the reactivity of resident lung cells such as alveolar macrophages. In these cells, the cyclic adenosine monophosphate content is much less increased by prostaglandin E2 and salbutamol when they are obtained from actively sensitized animals.

Anaphylaxis↗
PubMed1989

Antigen-induced bronchopulmonary alterations in the guinea pig: a new model of passive sensitization mediated by mouse IgE antibodies.

A selective model to study the IgE-mediated anaphylactic bronchoconstriction (BC) in the guinea pig is needed, since human asthma involves mainly this class of antibody. However, most procedures presently available for passive homologous or active sensitization lead to responses which are mediated both by IgE and IgG antibodies. In this study, we developed an anaphylactic model in which guinea pigs are passively sensitized with mouse ascitic fluid containing dinitrophenol (DNP)-specific IgE antibodies. Challenge of sensitized animals with DNP coupled to bovine serum albumin evokes a bronchoconstrictor response that is maximal 5 h after sensitization. The resulting anaphylactic BC is not blocked by the H1 histamine antagonist mepyramine, by the peptido-leukotriene antagonist FLP 55712 nor by the platelet-activating factor antagonist BN 52021 alone. However, when the sensitized animals are pretreated with the three drugs in combination, significantly reduced BC was observed upon challenge with the antigen. This latter result indicates that IgE-dependent BC involves the participation of different mediators, a characteristic shared in common with allergic asthma in human.

Animals↗
PubMed1989

Role of lipoxygenase metabolites for the hyper-responsiveness to platelet-activating factor of lungs from actively sensitized guinea pigs.

The contribution of lipoxygenase metabolites to active sensitization-induced lung hyper-responsiveness in the guinea pig was investigated. Active sensitization was performed by two injections of 10 micrograms of ovalbumin in 1 mg of AI(OH)3 at a 2-week interval. The i.a. administration of increasing doses (1, 100 and 1000 ng) of platelet-activating factor (PAF-acether) into isolated perfused lungs from actively sensitized guinea pigs was followed by an enhanced bronchoconstriction as compared to that observed in lungs from nonimmunized animals. PAF-acether stimulation of actively sensitized lungs was accompanied by histamine secretion and by an increased release of leukotriene (LT)-like material (as detected by bioassay using guinea pig tracheal strips superfused with the lung effluent and by a radioimmunoassay for LTC4). Maximal PAF-acether-induced lung responses were observed 7 days after the booster injection of the antigen and remained at a plateau for at least 4 months. Lung response to antigen challenge occurred in parallel with the increase of the level of circulating immunoglobulin G and with the development of hyper-responsiveness up to 7 days after the booster injection. Then, a progressive decrease in the antigen-induced bronchoconstriction and mediator release was observed. Lungs from animals in which the booster injection was omitted responded to PAF-acether in a similar fashion as lungs from nonimmunized guinea pigs, even though they underwent anaphylactic reaction upon antigen challenge. Enhanced bronchoconstriction, tracheal contraction, immunoreactive LTC4-like material release, but not histamine secretion were suppressed by BW 755C, a mixed cyclooxygenase and lipoxygenase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1988

Pharmacological profile of 48740 R.P., a PAF-acether antagonist.

The pyrrolo-thiazole derivative 48740 R.P. inhibited the platelet-activating factor (PAF-acether)-induced aggregation of human and rabbit platelets and was poorly effective against ADP- and arachidonic acid-induced platelet aggregation. 48740 R.P. prevented the activation of guinea-pig alveolar macrophages by PAF-acether, and the PAF-acether-induced thromboxane B2 production from guinea-pig lungs. 48740 R.P. (3 mg/kg i.v.) antagonized selectively in anaesthetized guinea-pigs the bronchoconstriction due to PAF-acether without affecting that due to acetylcholine, histamine, serotonin, thromboxane A2 analogue U-46,619 and arachidonic acid. A higher dose of 48740 R.P. (10 mg/kg i.v.) was required to block the thrombocytopenia and the leucopenia induced by PAF-acether in the propranolol-treated guinea-pigs. 48740 R.P. (30 mg/kg i.v.) antagonized the PAF-acether effects when bronchoconstriction was induced by aerosolized PAF-acether. 48740 R.P. is a selective antagonist of PAF-acether under in vitro and in vivo conditions.

Animals↗
PubMed1988

Interference of the Paf antagonist Ro 19-3704 with Paf and antigen-induced bronchoconstriction in the guinea-pig.

1. In vitro, Ro 19-3704, a structurally related antagonist of platelet-activating factor (Paf) inhibited selectively rabbit platelet aggregation. In vivo, administered intravenously, it inhibited bronchoconstriction, leukopenia, thrombocytopenia and the accompanying accumulation of platelet aggregates in guinea-pig lung microvessels induced by i.v. Paf. Administered by aerosol, Ro 19-3704 failed to inhibit bronchoconstriction, thrombocytopenia or leukopenia due to i.v. Paf. 2. Bronchoconstriction induced by Paf, in aerosol form, was blocked by Ro 19-3704 administered by the i.v. or aerosol route, which suggests that it interacts with pulmonary cells responsible for bronchoconstriction. 3. Ro 19-3704 has free radical scavenging properties, since it inhibited the production of superoxide anions by macrophages stimulated by Paf and by N-formyl-methionyl-leucyl-phenylalanine (FMLP). Ro 18-7715, another Paf antagonist and analogue of Ro 19-3704, failed to inhibit the production of superoxide anions by macrophages stimulated by FMLP at concentrations which were effective against Paf. 4. Administered intravenously, Ro 19-3704 failed to block bronchoconstriction induced by an i.v. injection of ovalbumin to guinea-pigs passively sensitized with anti-ovalbumin antiserum. Passive pulmonary anaphylaxis due to an aerosol of ovalbumin was blocked by i.v. Ro 19-3704.

Aerosols↗
PubMed1988

Involvement of PAF-acether in anaphylactic bronchoconstriction induced in guinea pigs by aerosolized antigen.

Bronchoconstriction following the aerosolization of PAF-acether or antigen to guinea pigs induces autodesensitization, but the responses to direct spasmogenic substances are not modified. Bronchoconstriction by PAF-acether is not reduced when it is aerosolized to passively sensitized animals previously desensitized by repeated inhalations of the allergen (ovalbumin). In contrast, when passively sensitized animals are initially desensitized to PAF-acether by repeated inhalations of this agonist, ovalbumin aerosolization induces a bronchoconstriction which is significantly reduced when compared with the response obtained in nondesensitized animals though, in this case, the response to aerosolized histamine is not modified. Thus, PAF-acether is released during intrapulmonary anaphylactic shock induced by aerosolized ovalbumin and can be a prime candidate for its development.

Aerosols↗
PubMed1988

Eosinophil recruitment into guinea pig lungs after PAF-acether and allergen administration. Modulation by prostacyclin, platelet depletion, and selective antagonists.

Intravenous administration of PAF-acether to the guinea pig induces bronchoconstriction, hypotension, intravascular platelet aggregation, endothelial disruption, and platelet and neutrophil diapedesis. These effects are followed within 1 h by an eosinophilic infiltration into the bronchial walls, which was also noted after the administration of antigen to passively sensitized guinea pigs. Bronchoconstriction and eosinophil infiltration are 2 major features of asthma, and selective bronchial eosinophilia characterizes late asthmatic reactions. We compared the histologic effects of PAF-acether 6 and 24 h after its intravenous injection with those of experimental passive anaphylactic shock, which is used as a model for asthma. Six hours after PAF-acether or antigen (ovalbumin) administration, a marked lung eosinophil infiltration, particularly in the bronchial walls, was noted, together with mucous plugs containing eosinophils in the bronchial lumen. Epithelial desquamation was followed after 24 h by mucous metaplasia of the bronchial epithelium. These effects were not observed when the inactive metabolite lyso-PAF was used. Our results agree fully with the suggestion that the eosinophil mediates the pathophysiology of bronchial asthma and releases materials toxic for the respiratory epithelium. Two PAF-acether antagonists (BN 52021 and WEB 2086) prevented the eosinophil infiltration triggered by PAF-acether and by antigen. When PAF-acether or ovalbumin were injected into guinea pigs after antiplatelet serum or prostacyclin, the eosinophil infiltration was significantly reduced, suggesting that platelets or another adenylate cyclase-sensitive cell are important for the subsequent PAF-acether-induced eosinophil infiltration. Our results support an essential role for PAF-acether in an experimental model of allergic asthma.

Allergens↗
PubMed1988

Active immunization induces lung hyperresponsiveness in the guinea pig. Pharmacologic modulation and triggering role of the booster injection.

In order to investigate whether bronchopulmonary hyperresponsiveness represents a unique property of sensitized lungs, we examined the responses of lungs from either actively sensitized, passively sensitized, or nonsensitized (control) guinea pigs to in vitro bronchoconstriction (BC) and release of thromboxane (TX) B2, 6-keto-PGF1 alpha, and histamine induced by platelet-activating factor (PAF-acether) or leukotriene (LT) D4. Guinea pigs were actively sensitized with 10 micrograms of either ovalbumin or Dermatophagoides farinae extract in AI(OH)3 injected intraperitoneally twice at a 2-wk interval. Seven days after the second injection (booster injection), the lungs were removed, ventilated, and perfused via the pulmonary artery with Krebs solution containing 2.5 g/L bovine serum albumin. In lungs from actively sensitized animals, BC was induced by significantly lower doses of PAF-acether and LTD4 than those required to elicit the same response in control preparations. In addition, sensitized lungs released more TxB2, 6-keto-PGF1 alpha, and histamine in response to PAF-acether and LTD4 than did control lungs. Increased mediator release was also observed upon challenge of lungs from actively sensitized animals with arachidonic acid and histamine. Lungs from guinea pigs passively sensitized with serum from actively sensitized animals did not exhibit increased responsiveness to PAF-acether as compared to control lungs. The hyperresponsiveness induced after booster injection of the antigen occurred concomitantly with an increase in the homocytotropic antibody titer (as measured by passive cutaneous anaphylaxis) and persisted for 3 months after sensitization, when the levels of circulating antibodies and lung response to antigen challenge returned to control values.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Interference by the novel PAF-acether antagonist WEB 2086 with the bronchopulmonary responses to PAF-acether and to active and passive anaphylactic shock in guinea-pigs.

The interaction between the triazolothienodiazepine WEB 2086 and the in vitro and in vivo bronchopulmonary effects of PAF-acether and active/passive anaphylaxis in the guinea-pig was studied. WEB 2086 (1-100 nM) inhibited PAF-acether (10-100 ng)-induced bronchoconstriction and TXB2 release from isolated and perfused guinea-pig lungs without affecting the response to 100 micrograms arachidonic acid. In addition, 1-10 microM WEB 2086 significantly reduced antigen-induced TXB2 and histamine release from lungs from actively and passively sensitized guinea-pigs. In the presence of the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA), mepyramine, methysergide, indomethacin and atropine, WEB 2086 (20-50 microM) inhibited by 30-40% the residual contraction of lung parenchyma strips from guinea-pigs actively sensitized by 0.1-10 micrograms antigen. In vivo, WEB 2086 (0.1-1 mg/kg) reversed or abolished the bronchoconstriction, hypotension, thrombocytopenia and leukopenia evoked by perfusion of PAF-acether (3 or 44 ng/kg per min). At 3 mg/kg, WEB 2086 also markedly decreased the bronchoconstriction and leukopenia induced by 100 micrograms/kg antigen in mepyramine (5 micrograms/kg)-treated passively sensitized guinea-pigs. In contrast, WEB 2086 was ineffective against active anaphylaxis in vivo. These results demonstrate that WEB 2086 antagonizes the bronchopulmonary effects due to PAF-acether and to anaphylactic shock in the guinea-pig.

Anaphylaxis↗