Effect of the PAF antagonists, CV-3988 and L-652, 731 on the pulmonary and hematological responses to guinea pig anaphylaxis

Danko, Gisela; Sherwood, J; Grissom, Beverly; Kreutner, William; Chapman, Richard W.

doi:10.1016/s0031-6989(88)80717-3

Cited by 14 publications

(6 citation statements)

References 23 publications

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“…However, as we have shown, the increased recovery of inflammatory cells in the BAL fluid following LTD., antagonist treatment was not reduced [26], Taken together, theses results suggest that 5'-LO products may be important for the late phase response but not for the AHR and inflammatory effects of allergen challenge in the BN rat. PAF is another potent membrane-derived lipid media tor which mimics many of the features of asthma [5,6], Similar to the present study, other workers have also demonstrated little effect of PAF antagonists against anti gen-induced anaphylaxis in actively sensitised animals [12,[24][25][26]. Some studies have shown an inhibitory effect of pre-treatment with selective PAF antagonists on allergeninduced AHR [26,27], while another study showed that endogenous PAF contributes little to allergen-induced AHR in animals [28].…”

Section: Discussionsupporting

confidence: 84%

Role of Cyclooxygenase and 5-Lipoxygenase Metabolites, Platelet-Activating Factor and 5-Hydroxytryptamine in Allergen-Induced Airway Responses in the Brown Norway Rat

Elwood¹,

Sakamoto²,

Barnes³

et al. 1994

Int Arch Allergy Immunol

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We determined the effects of selective inhibition of arachidonic acid metabolism via the cyclooxygenase and 5′-lipoxygenase pathways using flurbiprofen and BWA4C, respectively, of 5-hydroxytryptamine (5-HT) using methysergide and of platelet-activating factor (PAF) using WEB 2086 on the airway responses to ovalbumin (OA) aerosol in OA-sensitized Brown Norway rats. Twenty-one days after intraperitoneal injection of OA, rats were exposed to a 1% OA or saline aerosol. Only methysergide (10 mg/kg i.p.; 3 doses over 24 h) provided significant protection of the immediate response to OA. The increase in airway responsiveness to acetylcholine after OA exposure was not significantly altered by methysergide, flurbiprofen (10 mg/kg i.p.), BWA4C (50 mg/kg i.p.) and WEB 2086 (50 mg/kg i.p.) all given over 24 h prior to OA challenge. In addition, there was no effect on the increased recovery of eosinophils and lymphocytes in bronchoalveolar lavage fluid at 24 h. We conclude that 5-HT is an important mediator of the acute response to OA, but that 5-HT, lipoxygenase and cyclooxygenase products and PAF are unlikely to be involved in OA-induced airway hyperresponsiveness and inflammation in the Brown Norway rat.

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Section: Discussionsupporting

confidence: 84%

Role of Cyclooxygenase and 5-Lipoxygenase Metabolites, Platelet-Activating Factor and 5-Hydroxytryptamine in Allergen-Induced Airway Responses in the Brown Norway Rat

Elwood¹,

Sakamoto²,

Barnes³

et al. 1994

Int Arch Allergy Immunol

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“…Our claim that the booster injection determines whether the anaphylactic bronchoconstriction is or is not suppressed by BN 52021 explains the initial disappointing results obtained with PAF antagonists used against active anaphylactic bronchoconstriction and negates previous conclusions that PAF is not involved in active anaphylaxis (Detsouli et al, 1985;Lagente et al, 1985;Danko et al, 1988). This finding can probably be generalized.…”

Section: Discussionmentioning

confidence: 51%

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

Desquand

Lefort

Dumarey

et al. 1991

British J Pharmacology

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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.

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“…Also, WEB 2086 had no effect on the increased airway microvascular permeability in guinea-pigs after intravenous allergen challenge (Evans et al, 1988). Danko et al (1988) used the PAF receptor antagonists CV-3988 and L-652,731 and similarly showed no effects against intravenous antigen challenge in guinea-pigs, and concluded that PAF is not an important mediator of acute anaphylaxis in the guinea-pig. This is in accord with the work of Daffonchio et al (1987) who demonstrated that bronchoconstriction after antigen challenge in the guinea-pig is due primarily to histamine and leukotrienes.…”

Section: Eosinophils Recovered From Bronchoalveolar Lavagementioning

confidence: 99%

Prevention of non‐specific airway hyperreactivity after allergen challenge in guinea‐pigs by the PAF receptor antagonist SDZ 64–412

Havill

Valen²,

Handley³

1990

British J Pharmacology

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Allergen challenge by aerosol in sensitized guinea‐pigs elicited non‐specific airway hyperreactivity assessed by reactivity to i.v. histamine or acetylcholine. Airway hyperreactivity to histamine persisted for at least 48 h and was accompanied by pulmonary eosinophilia as determined by bronchoalveolar lavage cell analysis. Airway hyperreactivity was independent of vagal reflex mechanisms since it was not abrogated by bilateral vagotomy. The novel platelet‐activating factor (PAF) receptor antagonist SDZ 64–412 inhibited the development of airway hyperreactivity, as measured 24 h after aerosol allergen challenge, when given as a single treatment orally 2 h before allergen challenge. The PAF receptor antagonist WEB 2086 as well as methylprednisolone and ketotifen also showed efficacy in preventing development of airway hyperreactivity. Neither the two PAF antagonists nor ketotifen had any effect on bronchoalveolar lavage (BAL) eosinophil numbers. Methylprednisolone was the only substance which readily prevented eosinophil recruitment in addition to airway hyperreactivity. We conclude that allergen‐induced airway hyperreactivity in guinea‐pigs is inhibited by prophylactic anti‐asthma drugs and specific PAF receptor antagonists, thus demonstrating a pivotal role of PAF in this response. There was a lack of correlation between airway hyperreactivity and the presence of BAL eosinophils.

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Effect of the PAF antagonists, CV-3988 and L-652, 731 on the pulmonary and hematological responses to guinea pig anaphylaxis

Cited by 14 publications

References 23 publications

Role of Cyclooxygenase and 5-Lipoxygenase Metabolites, Platelet-Activating Factor and 5-Hydroxytryptamine in Allergen-Induced Airway Responses in the Brown Norway Rat

Role of Cyclooxygenase and 5-Lipoxygenase Metabolites, Platelet-Activating Factor and 5-Hydroxytryptamine in Allergen-Induced Airway Responses in the Brown Norway Rat

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

Prevention of non‐specific airway hyperreactivity after allergen challenge in guinea‐pigs by the PAF receptor antagonist SDZ 64–412

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