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Biomedical subjects

M Pretolani

Publications and source records attributed to M Pretolani.

64 records · Page 4Linked to original sources
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

A new method to evaluate extravascular albumin and blood cell accumulation in the lung.

A method was developed to evaluate blood volume, accumulation of extravascular albumin (ALBev), and platelet (PL) or polymorphonuclear neutrophil (PMN) sequestration in lungs after challenge with inflammatory agents. Erythrocytes (RBC), albumin, and PL or PMN, labeled with 99mTc, 131I, and 111In,-respectively, were injected intravenously into anesthetized and ventilated guinea pigs. The different parameters were calculated from in vivo lung and blood radioactivity values. When N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) was injected intravenously at 10 micrograms.kg-1, lung RBC content dropped by 14.7 +/- 1.8% (SE; n = 10), indicating a reduced lung blood volume, ALBev rose to 15.0 +/- 3.2% of the initial albumin vascular content, and the circulating PMN were sequestered by 9.2 +/- 1.7%. A transient PL sequestration was also observed 1 min after the injection of fMLP (13.1 +/- 2.0%, n = 7). During the infusion of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphorylcholine, the lung PL content rose dose dependently from 10.1 +/- 2.2% of the circulating pool with 3 ng.kg-1.min-1 to 54.9 +/- 20.1% with 44 ng.kg-1.min-1, the lung RBC content decreased by greater than 10%, and the ALBev increased beyond 16%. Our method allows the study of the correlations between cell entrapment and the variations of the albumin exchanges in the lung and may lead to a better understanding of the correlations between cell activation and edema.

Acetylcholine↗
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

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

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↗
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

Beneficial effects of defibrotide against myocardial ischemia and decline of beta-adrenoceptor function in the rabbit.

Defibrotide is a polydeoxyribonucleotide of mammalian origin which possesses profibrinolytic effect and PGI2-releasing capacity. Because of these properties, defibrotide has antithrombotic effects which are demonstrated in various experimental models of venous and arterial thrombosis. The present study indicates that defibrotide clearly protects against myocardial damage in the rabbit 3 days after total coronary artery occlusion. Furthermore, defibrotide prevents the decline of beta-adrenergic receptor function, a phenomenon related to excessive circulating catecholamines that occurs during the myocardial infarct. Defibrotide prevents the dramatic fall of creatine phosphokinase activity in the ischemic ventricle: metabolic changes which reflect changes in the cells affected by prolonged ischemia. Assumptions about the mode of action of defibrotide are given particularly in consideration of the interaction between the fibrinolytic activity and the PGI2-releasing capacity of this substance.

Animals↗
PubMedDate not supplied

Is platelet-activating factor involved in bronchopulmonary hyperresponsiveness?

Among the various lipid mediators, platelet-activating factor (PAF) is likely to participate in the development of inflammatory and allergic reactions. Indeed, PAF mimics the symptoms of anaphylactic shock and causes bronchial hyperreactivity in various species. The availability of specific PAF antagonists led to determination of the precise role of this mediator in experimental allergic situations. Here we provide evidence that the bronchopulmonary and inflammatory effects of PAF in the guinea-pig are different depending on the immunological status of the animals. Consequently, the search for novel PAF antagonists should take into account the experimental model developed for studying its implication in allergic reactions and in the accompanying airway inflammation.

Animals↗