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Biomedical subjects

V Lagente

Publications and source records attributed to V Lagente.

101 records · Page 6Linked to original sources
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↗
PubMed1985

Pulmonary anti-anaphylactic activity of clenbuterol tested on actively and passively sensitized guinea-pigs.

Clenbuterol, an adrenergic beta-mimetic agent free of cardiostimulant effects, prevents the release of histamine from isolated rat mast cells. We studied its anti-anaphylactic activity in guinea-pigs and compared it with that of isoprenaline. At doses inactive against the bronchoconstriction caused by 5HT, clenbuterol (3 micrograms/kg) and isoprenaline (0.1-0.3 micrograms/kg) prevented the bronchoconstriction due to 1 mg/kg ovalbumin infused into passively sensitized animals. Clenbuterol and isoprenaline (0.5-1 microM) inhibited by 40% the contractions of superfused parenchyma lung strips from actively sensitized animals, stimulated with 0.3, 1 and 10 micrograms of ovalbumin. When strips from passively sensitized animals were challenged in the organ bath, clenbuterol and isoprenaline (0.01 microM) reduced by 50% the contraction triggered by 10 micrograms/ml of ovalbumin. These concentrations of clenbuterol were ineffective against contractions caused by acetylcholine. Clenbuterol and isoprenaline (0.001-0.01 microM) inhibited the release of histamine and of thromboxane A2 triggered by ovalbumin (0.1, 1 and 10 micrograms) injected into isolated lungs from actively sensitized guinea-pigs indicating that the anti-anaphylactic properties of clenbuterol are independent from its smooth muscle relaxing activity.

Acetylcholine↗
PubMed1985

Desensitization to PAF-induced bronchoconstriction and to activation of alveolar macrophages by repeated inhalations of PAF in the guinea pig.

Guinea-pig alveolar macrophages are activated in the presence of PAF-acether (PAF), as shown by O2.- production, suggesting that these cells, abundant in the lungs, are involved in PAF-induced bronchoconstriction. Alveolar macrophages collected after in vivo desensitization to the bronchoconstrictor effect of PAF became refractory to it in vitro, whereas the O2.- production in response to f-met-leu-phe persisted, although it was diminished suggesting a partial cross-desensitization. A similar desensitization to PAF was also observed in alveolar macrophages in vitro, demonstrating a stimulus-specific process. This study suggests that alveolar macrophages may be involved in bronchoconstriction induced by aerosol of PAF.

Aerosols↗
PubMedDate not supplied

A tachykinin NK3 receptor antagonist, SR 142801 (osanetant), prevents substance P-induced bronchial hyperreactivity in guinea-pigs.

Aerosolized substance P (0.1 M, for 30 min) induced airway hyperresponsiveness in guinea-pigs 24 h after they were pre-treated with salbutamol (8.7 mM by aerosol for 10 min) and phosphoramidon (0.1 mM by aerosol for 10 min). This was displayed by an exaggerated response to the bronchoconstrictor effect of acetylcholine. A microvascular leakage hypersensitivity also occurred and was demonstrated by a potentiation of the plasma protein extravasation from bronchial vessels induced by histamine. The aim of this study was to investigate the effects of the non-peptide and potent tachykinin NK3 receptor antagonist, SR 142801 (osanetant), in comparison with those of the tachykinin NK1 and NK2 receptor antagonists, SR 140333 (nolpitantium) and SR 48968 (saredutant) respectively, on substance P. When given once at 1 mg/kg i.p. 45 min before exposure to substance P, SR 142801 prevented both hyperresponsiveness to acetylcholine and the potentiation of histamine-induced increase in microvascular permeability. SR 142801 did not exhibit any tachykinin NK1 or NK2 antagonistic activity in experiments on guinea-pig isolated airways, in vitro or in vivo. The results suggest that tachykinin NK3 receptors might be involved in these substance P-induced effects on airways.

Acetylcholine↗
PubMedDate not supplied

Protective effect of a specific platelet-activating factor antagonist, BN 52021, on bupivacaine-induced cardiovascular impairments in rats.

Administration of the local anaesthetic bupivacaine (1.5 or 2 mg/kg, i.v.) to rats elicited a marked decrease of mean arterial blood pressure (MBP) and heart rate (HR) leading to death (in 67% or 90% of animals respectively). Intravenous injection of the specific platelet-activating factor (PAF) antagonist BN 52021 (10 mg/kg), 30 min before bupivacaine administration (2 mg/kg i.v.) suppressed both the decrease of MBP and HR. In contrast, doses of 1 mg/kg BN 52021 given 30 min before or 10 mg/kg administered 5 min before i.v. injection of bupivacaine were ineffective. When BN 52021 (20 mg/kg i.v.) was injected immediately after bupivacaine (2 mg/kg), a partial reversion of the decrease of MBP and HR was observed, whereas the dose of 10 mg/kg was ineffective. A partial recovery of bupivacaine-induced ECG alterations was observed after pretreatment of the rats with BN 52021. Since the administration of BN 52021, at all doses studied, did not alter MBP and HR at the doses used, the bulk of these results clearly demonstrate a protective action of BN 52021, a specific antagonist of PAF, against bupivacaine-induced cardiovascular toxicity. Thus, consistent with its direct effect on heart, PAF appears to be implicated in bupivacaine-induced cardiovascular alterations.

Anesthesia↗
PubMedDate not supplied

TIMP-1 is a key factor of fibrogenic response to bleomycin in mouse lung.

Pulmonary fibrosis is characterized by the excessive deposition of extracellular matrix in the interstitium, resulting in respiratory failure. The role of remodeling mediators such as metalloproteinases (MMPs) and their inhibitors (TIMPs) in the fibrogenic process remains misunderstood. We investigated MMP-9, MMP-2, TIMP-1, TIMP-2 and TIMP-3 in the fibrotic response to bleomycin of fibrosis prone C57BL/6J and fibrosis resistant BALB/c mice. Mice were administered with 0.1 mg bleomycin by intranasal administration. Either 24 h or 14 days after, the mice were anesthetized and underwent either bronchoalveolear lavage (BAL) or lung removal. Collagen deposition in lung tissue was determined by hydroxyproline measurement, MMP activity was analyzed by zymography, and other mediators were analyzed by ELISA. TIMP-1 was localized in lung sections by immunohistochemistry and real time PCR was performed to gene expression in lung. Non parametric Mann-Whitney and Spearman tests were used for statistical analysis. Fourteen days after bleomycin administration, hydroxyproline assay and histological study revealed that BALB/c mice developed significantly less fibrosis compared to C57BL/6J mice. At day 1, bleomycin enhanced TIMP-1, MMP-2 and MMP-9 protein levels in BALF, and induced corresponding genes in lung tissue of both strains. The rise of Timp-1, Mmp-9 and Mmp-2 gene levels were significantly stronger in lungs of C57BL/6J, whereas gelatinase activities of MMP-2 and MMP-9 were similar. Immunohistochemistry revealed that TIMP-1 macrophages and epithelial cells were prominent TIMP-1 producers in both strains. At day 14, neither MMP-2 nor MMP-9 levels exhibited strain-dependent protein level or gene expression, although TIMP-1 was strongly associated with fibrosis. Interestingly, bleomycin induced neither Timp-2 nor Timp-3 in lung tissue at any time of the study. The present study shows that early altered regulation of TIMP-1 following bleomycin administration may be involved in bleomycin-induced pulmonary fibrosis.

Animals↗
PubMedDate not supplied

Type 4 phosphodiesterase-dependent pathways: role in inflammatory processes.

Type 4 phosphodiesterases (PDE4) belong to a superfamily of at least 11 isozymes catalyzing the hydrolysis of cyclic AMP (cAMP) and/or cyclic GMP (cGMP). PDE4 regulate intracellular levels of cAMP and are the predominant PDE expressed in inflammatory cells. Elevation of cAMP produces the inhibition of different inflammatory processes, such as cellular trafficking, cytokine release or reactive oxygen species production. But recent papers showed that the involvement of PDE4 in inflammatory mechanisms cannot be completely attributed to a cAMP-dependent pathway. The wide range of inflammatory mechanisms controlled by PDE4 designated these enzymes as a good target for anti-inflammatory compounds. PDE4 inhibitors have been demonstrated to be very potent in the treatment of chronic inflammatory diseases like asthma or chronic obstructive pulmonary disease (COPD) but their therapeutic window has yet to be improved.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMedDate not supplied

Influence of interleukin-4 and platelet-activating factor on the Fc epsilon RII/CD23 expression on human monocytes.

Human recombinant interleukin-4 (IL-4) induces the expression of the low-affinity receptor for IgE (Fc epsilon RII/CD23) on human normal monocytes as assessed by flow cytometry. Also, platelet-activating factor (PAF) induces a time- and dose-dependent increase in Fc epsilon RII/CD23 expression, which is maximal with 1 microM PAF and after a 24-h incubation period. Under similar experimental conditions, lyso-PAF (1 microM) has no effect on Fc epsilon RII/CD23 expression. The PAF-induced Fc epsilon RII/CD23 expression on human monocytes is inhibited by two unrelated antagonists of the mediator, namely BN 52021 and BN 50730, but is not significantly affected when the cells are incubated in the presence of a rabbit anti-IL-4 antiserum. The IL-4-induced Fc epsilon RII/CD23 is abolished in the presence of the anti-IL-4 antiserum and slightly (not significantly) reduced when BN 52021 or BN 50730 is added to the incubation medium. These results suggest that PAF regulates Fc epsilon RII/CD23 expression and may indicate a new role for this autacoid in allergic diseases.

Antigens, Differentiation, B-Lymphocyte↗