Biomedical subjects

J Lefort

Publications and source records attributed to J Lefort.

At least 37 records · Page 2Linked to original sources

PubMed1996

Effect of cyclo-oxygenase inhibitors and modulators of cyclic AMP formation on lipopolysaccharide-induced neutrophil infiltration in mouse lung.

1. The adult respiratory distress syndrome (ARDS) is an acute lung inflammation developed after direct or indirect contact with pathogenic agents. In the present study, a mouse model was developed to mimic this condition using aerosolized bacterial lipopolysaccharide (LPS) and to investigate the mechanisms involved in the lung inflammatory response. 2. Inhalation of LPS led to a time and dose-dependent increase in tumour necrosis factor-alpha (TNF-alpha) production and neutrophil recruitment into the bronchoalveolar lavage fluid (BALF) of Balb/c mice. Under the same conditions, neutrophil infiltration was also found in the BALF of the LPS-sensitive mouse strain C3H/HeN, but was absent in the LPS-resistant strain C3H/HeJ. Intranasal administration of murine recombinant TNF-alpha also triggered neutrophil recruitment. 3. One hour after inhalation of LPS, half of the maximal level of TNF-alpha was measured in the BALF, but only a few neutrophils were detected at this time. The peak TNF-alpha concentration was reached at 3 h, when the neutrophil amount started to increase. At 24 h, maximal neutrophil number was found in the BALF and TNF-alpha was no longer present. 4. Pretreatment of mice under different experimental conditions demonstrated that: (a) cycloheximide almost completely blocks both neutrophil recruitment and TNF-alpha production; (b) anti TNF-alpha antibodies block neutrophil recruitment; (c) indomethacin or aspirin enhance by two fold neutrophil recruitment; (d) indomethacin significantly increases TNF-alpha production 1 h after inhalation of LPS; (e) dibutyryl cyclic AMP and prostaglandin E2 (PGE2) block both neutrophil recruitment and TNF-alpha production. 5. It is concluded that aerosolized LPS in mice triggers an acute lung inflammation which can be used as a potential model of inhalational ARDS and that, strategies leading to the elevation of cyclic AMP levels in vivo can be effective in modulating LPS-induced TNF-alpha synthesis and neutrophil recruitment.

Administration, Inhalation↗

PubMed1996

Inhibition of airways inflammation by dexamethasone is followed by reduced bronchial hyperreactivity in BP2 mice.

BACKGROUND: Infiltration of inflammatory cells in the airways is a constant characteristic of asthma and is considered to result in bronchial hyperreactivity (BHR). We have recently developed a model of BHR using a selection of mice, named BP2, which display eosinophil-dependent BHR following antigen challenges. An anti-IL-5 antibody suppressed antigen-induced eosinophil recruitment to the airways and BHR in BP2 mice. OBJECTIVE: To investigate the implication of infiltrated inflammatory cells in the induction of BHR in mice. METHODS: The effects of glucocorticosteroid dexamethasone on airways eosinophilia and BHR were observed. RESULTS: Administration of dexamethasone at the dose of 1.25 mg/kg i.p. 1 h before each of four antigen provocations suppressed the airways eosinophilia and BHR in response to intravenous 5-HT and to aerosolized methacholine, as well as IL-5 production in the BALF and in the serum. By contrast, dexamethasone failed to reduce anaphylactic bronchoconstriction. CONCLUSIONS: These results suggest that dexamethasone exerts its inhibitory effects on antigen-induced airways eosinophilia in mice by inhibiting IL-5 production, but that it does not block the liberation of anaphylactic mediators in mice.

Anaphylaxis↗

PubMed1995

Eosinophil recruitment into the respiratory epithelium following antigenic challenge in hyper-IgE mice is accompanied by interleukin 5-dependent bronchial hyperresponsiveness.

A murine model for antigen-induced bronchial hyperreactivity (BHR) and airway eosinophilia, two hallmarks of asthma, was developed using ovalbumin-immunized mice, which produce large amounts of IgE (named BP2, "Bons Producteurs 2," for High Line of Selection 2). A single intranasal ovalbumin challenge failed to modify the bronchial responses, despite the intense eosinophil recruitment into the bronchoalveolar lavage fluid and airways. When mice were challenged twice a day for 2 days or once a day for 10 days, BHR in response to i.v. 5-hydroxytryptamine or to inhaled methacholine was induced in BP2 mice but not in BALB/c mice. Histological examination showed that eosinophils reached the respiratory epithelium after multiple ovalbumin challenges in BP2 mice but remained in the bronchial submucosa in BALB/c mice. Total IgE titers in serum were augmented significantly with immunization in both strains, but much more so in BP2 mice. Interleukin 5 (IL-5) titers in serum and bronchoalveolar lavage fluid of BP2 mice were augmented by the antigenic provocation, and a specific anti-IL5 neutralizing antibody suppressed altogether airway eosinophilia and BHR, indicating a participation of IL-5 in its development. Our results indicate that the recruitment of eosinophils to the airways alone does not induce BHR in mice and that the selective effect on BP2 mice is related to their increased IgE titers associated with antigen-driven eosinophil migration to the epithelium, following formation and secretion of IL-5.

Animals↗

PubMed1994

Albumin exchange and inflammatory cell recruitment in lungs of antigen-challenged guinea pigs: role of histamine.

Microvascular albumin exchange and sequestration of inflammatory cells into the lungs of anesthetized guinea pigs immunized to ovalbumin were evaluated using radioactive tracers. Increased exchange of radiolabeled (*) albumin from airways to blood was noted in immunized and boosted animals under basal conditions. After the intratracheal injection of 300 micrograms of ovalbumin, an additional increase in exchange through epithelium occurred, since the rate of appearance of *albumin in blood was enhanced compared with control (140 +/- 30 vs. 54 +/- 20% in 1 h). The augmentation of lung content in extravascular *albumin compared with control (16.2 +/- 4.0 vs. 5.9 +/- 1.6%) indicates that transendothelial exchange was also facilitated. Concomitment with the sequestration of *platelets into the lungs of antigen-challenged sensitized animals (59.2 +/- 20% in 1 h), leukocytes (> 60% polymorphonuclear neutrophils) did not marginate. Histamine released during antigenic shock might promote leukocyte demargination from the vascular bed through its vasomotor effect and/or by inhibiting leukocyte activation and consequently may counteract the effects of other inflammatory mediators acting to sequester neutrophils. In confirmation, perfusion of histamine to the immunized animals induced demargination of lung leukocytes. Histamine antagonists prevented the increased exchange of *albumin through the epithelial and endothelial barriers and uncovered *leukocyte sequestration (100.7 +/- 28.9% in 1 h) in the lungs of antigen-challenged animals. Histamine antagonists may favor antigen-induced leukocyte sequestration in the lungs by preventing the effects of endogenous histamine on capillary recruitment and blood flow.

Animals↗

PubMed1994

Role of eosinophil activation in the bronchial reactivity of allergic guinea pigs.

Ovalbumin inhalation by sensitized guinea pigs induced a marked increase in the number of eosinophils (0.89 +/- 0.18 to 5.45 +/- 0.77 x 10(5)/ml, n = 10, p < 0.05) and elevations in the amounts of protein and eosinophil-derived major basic protein (MBP) (1,010.7 +/- 184.9 to 4,116.6 +/- 973.0 ng/ml, n = 10, p < 0.05) recovered by bronchoalveolar lavage (BAL). In contrast, no changes in the levels of eosinophil peroxidase (EPO) or in the sensitivity of the airways to bronchoconstriction induced by methacholine were detected. However, when ovalbumin-exposed guinea pigs received an intratracheal instillation of 1 microgram leukotriene (LT)B4 30 min prior to methacholine provocation, elevated levels of EPO and MBP in the BAL fluid and a marked bronchial hyperreactivity to methacholine were noted when compared with saline-challenged LTB4-injected animals (p < 0.05). In contrast, the intratracheal instillation of 1 or 3 micrograms platelet-activating factor (PAF) did not significantly modify the bronchial reactivity to methacholine or the levels of EPO and MBP. PAF and LTB4 induced similar enhancements in the amount of protein in BAL fluids from antigen-exposed guinea pigs, suggesting that increased endothelial/epithelial permeability does not account for hyperreactivity. A significant correlation between the levels of EPO or MBP and the intensity of the bronchial responsiveness to methacholine were shown in ovalbumin-challenged guinea pigs, irrespective of their subsequent treatment, i.e., either with PAF or with LTB4 or with their vehicle (r = 0.579, p = 0.0002 and r = 0.330, p = 0.049, n = 36 for EPO and MBP, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Compound PCA-4248 interferes with bronchopulmonary anaphylaxis and with in vitro hyperresponsiveness to platelet-activating factor.

The intravenous (i.v.) or oral administration of the platelet-activating factor (PAF) antagonist, PCA-4248, to guinea-pigs blocked selectively the bronchoconstriction induced by PAF, as well as the accompanying thrombocytopenia and leucopenia. In addition, PCA-4248 i.v. or intratracheal (i.t.) administration blocked the bronchoconstriction caused by the i.t. instillation of PAF. As in the case of other PAF antagonists, bronchoconstriction caused by the i.t. instillation of antigen was only inhibited by PCA-4248 in guinea-pigs that did not receive a booster injection of antigen during sensitization whereas the booster injection of antigen made anaphylactic bronchoconstriction resistant to the compound. In vitro, when lungs from non-sensitized guinea-pigs were perfused with Krebs-bovine serum albumin (BSA) solution supplemented with PCA-4248, bronchoconstriction and the formation of thromboxane A2 by PAF were blocked. In this in vitro model of perfused lungs, active sensitization with a booster injection of antigen leads to bronchopulmonary hyperresponsiveness to PAF and failure of other PAF antagonists to inhibit the effects of PAF itself. Surprisingly, in lungs isolated from actively sensitized and boosted guinea-pigs, PCA-4248 blocked the effects of PAF, indicating that this compound possesses additional original properties in this model.

Anaphylaxis↗

PubMed1993

Inhibition by nedocromil sodium of recombinant human interleukin-5-induced lung hyperresponsiveness to platelet-activating factor in actively sensitized guinea pigs.

BACKGROUND: The intratracheal instillation of recombinant human interleukin-5 (rhIL-5) into isolated lungs from sensitized and antigen-boosted guinea pigs is followed by enhanced responses to platelet-activating factor (PAF). METHODS: Modulation by nedocromil sodium of rhIL-5-dependent hyperresponsiveness to PAF was investigated. Perfused lungs from guinea pigs actively sensitized to ovalbumin were injected intratracheally with 300 ng rhIL-5 followed by PAF (10 and 100 ng intraarterially). RESULTS: No inhibition of rhIL-5-induced increased bronchoconstriction and release of thromboxane (TX)B2 and histamine by PAF was observed when nedocromil sodium (10 mumol/L) was perfused into the lungs. In contrast, when guinea pigs were treated for 2 days (30 mg/kg twice a day), eosinophil recruitment into the bronchoalveolar lavage fluid and hyperresponsiveness to PAF were markedly reduced (100% [p < 0.001]; around 70% [p < 0.05] and around 90% [p < 0.001] inhibition for bronchoconstriction, TXB2 and histamine release, respectively). CONCLUSION: Our results indicate that nedocromil sodium prevents the rhIL-5-induced lung hyperresponsiveness to PAF and the eosinophil migration into the airways only when it is administered in vivo. It is thus suggested that nedocromil sodium interferes with the development of airway inflammation by inhibiting the recruitment in the lung of a target on which PAF and IL-5 interact.

Animals↗

PubMed1993

Interference of a neutrophil recruitment inhibitory factor upon the accumulation of inflammatory cells and airway hyperreactivity in sensitized guinea-pigs after intranasal antigen challenge.

1. A neutrophil recruitment inhibitory factor (NRIF) recovered from the crude supernatant of lipopolysaccharide (LPS)-stimulated macrophages inhibited neutrophil migration following both intratracheal and intravenous administration of LPS, but did not alter the pattern of leukopenia/leucocytosis induced by intravenous LPS. 2. The correlation between airway infiltration by inflammatory cells and hyperreactivity in lungs from actively sensitized and challenged guinea-pigs was investigated by use of NRIF. 3. Increased eosinophil counts were found in the bronchoalveolar lavage fluid from guinea-pigs sensitized with 10 micrograms ovalbumin and challenged at day 14 by the intranasal administration of the antigen. The increase was evident 5 h after challenge and persisted at 24 h. Neutrophil numbers were also increased at this time. Pretreatment with NRIF suppressed the leucocyte increase in the bronchoalveolar lavage fluid. 4. Bronchoconstriction and histamine release induced by 3 ng PAF injected into the isolated lungs were increased in challenged guinea-pigs as compared to sensitized but unchallenged controls. Pretreatment of the animals with NRIF did not interfere with this response, but significantly reduced the bronchoconstriction induced by ovalbumin injection. 5. Even though the increased number of inflammatory cells in bronchoalveolar lavage and airway hyperresponsiveness were concomitant, NRIF inhibited cellular infiltration but failed to alter airway hyperreactivity to PAF, demonstrating that these events may occur independently. Conversely, the inhibition of antigen-induced bronchoconstriction by NRIF suggests that this response is dependent upon the emigration of granulocytes.

Administration, Intranasal↗

PubMed1993

Intratracheal E. coli lipopolysaccharide induces platelet-dependent bronchial hyperreactivity.

Bronchial hyperresponsiveness (BHR) characterizes asthma and accompanies respiratory infections. Because endotoxin [lipopolysaccharide (LPS)] induces either hyper- or hyporesponsiveness of the guinea pig airways and protects against bronchopulmonary anaphylaxis in sensitized guinea pigs, we compared the effects of the intratracheal administration of Escherichia coli LPS on bronchopulmonary responsiveness to intravenous serotonin or acetylcholine in sensitized and nonsensitized guinea pigs. LPS (1 mg) induced BHR within 1-2 h, with a threefold increase in the bronchial response after serotonin challenge in both groups (n = 6; P < 0.005) and a marked influx of neutrophils into the perivascular and peribronchial connective tissue and the bronchoalveolar lavage fluid. This BHR was not leukocyte dependent, since it was still observed in animals depleted of circulating leukocytes with vinblastine and was not modified by antineutrophil serum, unless platelet counts were < 100,000/mm3. This suggested that LPS-induced BHR involves platelets, and indeed antiplatelet serum, which depleted platelets, or prostacyclin, which inhibited platelets, was effective in suppressing BHR. Neither aspirin, mepyramine, nor the platelet-activating factor antagonist WEB 2170, administered before LPS instillation, prevented BHR, whereas the association of methysergide, mepyramine, and aspirin was effective, without modifying platelet and leukocyte counts. This association has been shown to prevent the release of ATP by ex vivo platelets. Our results suggest that platelets or a platelet-derived product mediates LPS-induced BHR.

Acetylcholine↗

PubMed1993

Effect of active sensitization on the bronchopulmonary responses to tachykinins in the guinea pig. Modulation by peptidase inhibitors.

The i.v. administration of substance P (SP, 0.25-16 micrograms/kg) or of the selective metabolic stable NK-1 agonist, [Glp6,Pro9]SP-(6-11) (septide, 0.03-0.25 microgram) to atropine-treated guinea pigs or to isolated perfused lungs triggered a dose-dependent bronchoconstriction, which was enhanced in animals actively sensitized to ovalbumin. In vivo, bronchial hyper-responsiveness was restricted to SP and to septide, inasmuch as neurokinin A (0.06-1 microgram/kg)- or capsaicin (0.5-32 micrograms/kg)-induced bronchoconstriction were not modified. In contrast, isolated lungs from sensitized guinea pigs exhibited an increased bronchoconstriction also in response to capsaicin (0.01-10 micrograms), which was inhibited by atropine in the medium. Pretreatment of actively sensitized guinea pigs either with indomethacin plus mepyramine, the lipoxygenase inhibitor BW A4C or with the platelet-activating factor antagonist SR 27417, did not modify bronchial hyper-reactivity to SP. Captopril (5 mg/kg i.v.), but not thiorphan (0.8 mg/kg i.v.), increased the SP-induced bronchoconstriction in actively sensitized animals, whereas both inhibitors were equally effective in nonsensitized guinea pigs. Thiorphan, however, did not modify the in vivo response to septide. Our results demonstrate that guinea pigs sensitized to ovalbumin exhibit bronchial hyperreactivity to SP, but not to neurokinin A, as compared to nonsensitized animals, suggesting a decrease in the neutral endopeptidase activity in the airways brought by the immunization. However, the results obtained by using septide indicate that other mechanisms may be involved in the bronchial hyper-reactivity to SP.

6-Ketoprostaglandin F1 alpha↗

PubMed1992

Inhibition by azelastine of the effects of platelet-activating factor in lungs from actively sensitised guinea-pigs.

The effect of azelastine on platelet-activating factor (PAF)-induced bronchoconstriction and mediator release in isolated lungs from actively sensitised guinea-pigs was investigated. Guinea-pigs were actively sensitised with two s.c. injections of 10 micrograms ovalbumin in 1 mg Al (OH)3 at a 2-week interval. One week after the second injection, the lungs were removed and challenged intra-arterially with PAF or arachidonic acid. In some experiments lungs from non-immunised guinea-pigs were injected with PAF or histamine. Bronchoconstriction, the release of thromboxane (TX)B2 or leukotriene (LT)-like material and the histamine content of the effluent were evaluated. Azelastine was given s.c. at 10 or 100 micrograms/kg, 4 h before lung removal. Azelastine (100 micrograms/kg) did not inhibit PAF-induced bronchoconstriction and mediator release from lungs from non-immunised guinea-pigs. In contrast, the hyperresponsiveness to 1 ng PAF observed in lungs from actively sensitised animals was dose dependently inhibited by azelastine. Azelastine did not reduce the histamine-induced bronchoconstriction and consequent TXB2 release from lungs from immunised guinea-pigs, indicating that the protective effect exerted against hyperresponsiveness to PAF was not due to histamine antagonism. Azelastine also reduced arachidonic acid-induced bronchoconstriction and LT-like material release from sensitised lungs, regardless of the presence of indomethacin. These results suggest that inhibition of lung hyperresponsiveness to PAF by azelastine may result from an interference with leukotriene synthesis.

Animals↗

PubMed1992

Pertussis toxin induces bronchopulmonary hyperresponsiveness in guinea-pigs while antagonizing the effects of formyl-L-methionyl-L-leucyl-L-phenylalanine.

Pertussis toxin injected i.v. at 0.8-20 micrograms/kg markedly enhanced bronchoconstriction induced by the i.v. administration of histamine or serotonin (5-HT) (0.5-16 micrograms/kg) to propranolol-treated guinea-pigs, under conditions where propranolol or pertussis toxin alone were poorly effective. In contrast, bronchoconstriction and the accompanying leukopenia induced by the i.v. administration of the secretagogue formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) were suppressed by pertussis toxin. Bronchoconstriction induced by histamine or 5-HT was not enhanced when perfused lungs from pertussis toxin-treated guinea-pigs were studied in vitro, under conditions where bronchoconstriction and thromboxane A2 release evoked by fMLP were suppressed. Pertussis toxin negatively modifies signal transduction in cells involved in the lung responses to fMLP both in vivo and in vitro, but positively and only in vivo it modifies signal transduction in cells involved in the lung responses to the direct constricting agents histamine and 5-HT. As hyperresponsiveness to histamine and 5-HT were exclusively found in vivo, the target for pertussis toxin is probably not the adrenergic nor the cholinergic systems, since neither hexamethonium, isoprenaline, atropine nor vagotomy were effective. In addition, since dexamethasone and nedocromil sodium were inactive and enrichment of bronchoalveolar lavage with inflammatory cells was not noted, despite lung invasion by neutrophils and lymphocytes, acute inflammation does not account for pertussis toxin-induced hyperresponsiveness.

Animals↗

PubMed1992

Guinea-pig treatment with pertussis toxin suppresses macrophage-dependent bronchoconstriction by fMLP and fails to inhibit the effects of PAF.

1. Bronchoconstriction and thromboxane B2 (TxB2) release following the intra-tracheal administration of the secretagogue N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) to lungs from pertussis toxin-treated guinea-pigs in vivo and in vitro were inhibited as compared to saline-treated animals, under conditions where the responses to PAF were modified less effectively. 2. The cell target accounting for bronchoconstriction by fMLP and for inhibition by pertussis toxin is located in the airways and is probably the alveolar macrophage. Indeed (a) fMLP-induced superoxide anions and TxB2 formation by alveolar macrophages were inhibited by pertussis toxin given in vivo; (b) Gi proteins of membranes from alveolar macrophages were ADP-ribosylated in vivo by pertussis toxin and (c) bronchoconstriction and TxB2 release in response to the intra-tracheal administration of fMLP to lungs from pertussis toxin-treated animals were restored when alveolar macrophages from control guinea-pigs were transferred into the airways of pertussis toxin-treated animals before lung isolation. 3. Pertussis toxin administered to guinea-pigs in vivo, reduced the subsequent TxB2 formation and superoxide anion release by alveolar macrophages stimulated with PAF, but failed to inhibit PAF-induced bronchoconstriction. 4. Formation of TxB2 by alveolar macrophages following the intra-tracheal administration of fMLP accounts for bronchoconstriction and requires pertussis toxin-sensitive Gi proteins. PAF operates via a different mechanism, which is independent of Gi-like protein and involves mediators other than TxB2 and superoxide anions.

Adenosine Diphosphate Ribose↗

PubMed1992

Effect of human recombinant interleukin-5 on in vitro responsiveness to PAF of lung from actively sensitized guinea-pigs.

1. The intra-tracheal (i.t.) administration of human recombinant interleukin-5 (rhIL-5; 100 or 300 ng) to isolated perfused lungs from guinea-pigs actively sensitized to ovalbumin induced an increased bronchoconstriction and release of thromboxane A2 (TXA2) and histamine into the lung effluent following the subsequent (10 min) intra-arterial injection of platelet-activating factor (PAF). Lung responses to 5-hydroxytryptamine were unaffected by rhIL-5. 2. Hyperresponsiveness to PAF was observed when the lungs were obtained from guinea-pigs used 2 or 7 days after a booster injection of the antigen and, to a lower extent, when they were from animals sensitized by a single antigen administration. By contrast, rhIL-5 did not modify the responses to PAF of lungs from passively sensitized or from adjuvant-treated guinea-pigs, suggesting that immunological stimulation is required to allow the expression of synergism between rhIL-5 and PAF. 3. Guinea-pigs killed 2 and 7 days after the booster injection of the antigen exhibited a marked increase in the number of eosinophils in the bronchoalveolar lavage fluid (BAL), as compared to non-sensitized animals. 4. Our results demonstrate that rhIL-5 and PAF act synergistically to induce enhanced bronchoconstriction and mediator release exclusively when lungs are obtained from guinea-pigs sensitized once to ovalbumin and then boosted. Since recruitment of eosinophils into the airways and the development of hyperresponsiveness to PAF are concomitant, it is suggested that eosinophils are the target cells for interaction between rhIL-5 and PAF.

Animals↗

PubMed1992

Thromboxane A2 accounts for bronchoconstriction but not for platelet sequestration and microvascular albumin exchanges induced by fMLP in the guinea pig lung.

When injected i.v. to guinea pigs, the granulocyte secretagog N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) induces bronchoconstriction (BC), lung platelet sequestration and increased transendothelial albumin exchanges in lungs. We evaluated BC and the variations of the lung contents in radiolabeled platelets, erythrocytes and extravascular albumin, as measurements of platelet lung entrapment, reduction of lung blood volume and increase of transendothelial albumin exchanges, respectively. Trimetoquinol, a thromboxane A2 (TXA2)-endoperoxide receptor antagonist, inhibited BC and platelet entrapment by lungs induced by fMLP, but protection was nonspecific because it also suppressed BC by histamine. The specific TXA2 synthetase inhibitor/endoperoxide receptor antagonist ridogrel suppressed BC and reduced lung platelet entrapment, but failed to prevent the increase of extravascular albumin and the decrease of erythrocyte lung contents due to fMLP. Consequently, the fMLP-induced increase of vascular albumin exchanges and reduction of lung blood volume are TXA2-independent. Aspirin prevented BC, but failed to suppress lung platelet entrapment by fMLP, indicating that in vivo platelet activation is not TXA2-dependent, even though the levels of circulating TXB2, the stable metabolite of TXA2, were increased after fMLP concomitantly with that of 6-keto-prostaglandin (PG)F1 alpha, the stable metabolite of PGI2. The ridogrel-treated animals showed reduced blood level of TXB2 and increased levels of 6-keto-PGF1 alpha after fMLP challenge. Blocking the cyclooxygenase pathway with aspirin prevented ridogrel-induced protection against lung platelet sequestration after fMLP, supporting the concept that rechanneling of arachidonate metabolism toward protective prostaglandins accounts for protection by ridogrel.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1991

Dissociation between LPS-induced bronchial hyperreactivity and airway edema in the guinea-pig.

The interactions between LPS-induced bronchial hyper-reactivity (BHR) and lung inflammation (LI) were investigated. LPS-induced LI was assessed with the augmented alveolo-capillary permeability (ACP) and with the increased migration of neutrophils into the broncho-alveolar lavage fluid. BHR was defined as the increase in the response to a standard dose of serotonin. Mepyramine and the PAF antagonist WEB 2170 blocked LPS-induced increase of ACP, whereas aspirin was inactive. By contrast, neither LPS-induced neutrophil attraction to airways, nor LPS-induced HBR were inhibited by these agents. Our results indicate that LPS-induced edema and BHR are dissociated.

Animals↗

PubMed1991

The effect of cetirizine on antigen-dependent leucopenia in the guinea-pig.

1. Intravenous administration of ovalbumin (1 mg kg-1) to guinea-pigs that had previously been injected with 3.5 x 10(9) platelets from actively sensitized animals induced an approximately 40% decrease in the number of circulating leucocytes 30-60 min later, whereas the number of platelets was not affected. 2. In contrast, there was no change in the leucocyte number following antigen challenge of guinea-pigs that had received platelets from non-immunised animals. 3. This platelet-dependent leucopenia was inhibited by prior treatment of the recipient animal with cetirizine (10-30 mg kg-1, i.v.). Terfenadine (50 mg kg-1, p.o.) and mepyramine (2 mg kg-1, i.v.) were completely inactive in this respect. All doses of anti-histamines were used at concentrations which completely inhibited the bronchoconstriction to an i.v. injection of 5 micrograms kg-1 of histamine. 4. The site of action of cetirizine is most likely to be the platelet as leucopenia induced by the neutrophil agonists leukotriene B4 (LTB4) (30 ng kg-1) and platelet activating factor (PAF) (30 ng kg-1) were not modified by cetirizine treatment. 5. In these experiments, we failed to support a role for lipoxygenase products as mediators of the platelet-dependent leucopenia, as the selective lipoxygenase inhibitor BWA4C (50 mg kg-1, p.o.) was ineffective. 6. Our present results confirm and extend previous data demonstrating that antigen stimulated platelets can induce leucopenia in non-immunised animals and this can be inhibited by the anti-allergic agent, cetirizine, by an action which is probably unrelated to its anti-histamine properties. The precise nature of the platelet derived factor(s) and their target of action remains to be determined.

Animals↗

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↗