ovalbumin and phenidone

Eosinophil infiltration into bronchoalveolar areas of the lung has been assessed in guinea pigs sensitized to ovalbumin (OA) and then challenged with the aerosolized antigen. Cell content, histamine, and guinea pig albumin (GPA) have been measured in bronchoalveolar lavage (BAL) fluid from these animals. Extensive eosinophil accumulation resulted from sensitization followed by OA challenge; monocytes that initially accounted for greater than 80% of the BAL cells remained essentially constant, and neutrophils comprised less than 3% of the population throughout. Eosinophils were elevated at 3 h, peaked with a fivefold increase at 24 h, and remained elevated for at least 7 days. Histopathologic changes observed in lungs taken from sensitized guinea pigs 24 h after OA challenge confirm this eosinophilia. Increased histamine and GPA were detected only at 5 min. Oral treatment with betamethasone (ED50 = 0.4 mg/kg), phenidone (ED50 = 15 mg/kg), Sch 37224 (ED50 = 0.5 mg/kg), and WEB 2086 (ED50 = 4 mg/kg) decreased eosinophil accumulation in the BAL fluid, indicating roles for 5-lipoxygenase products and PAF in this multimediator-dependent model of allergic inflammation. On the other hand, 4 mg/kg of indomethacin increased total cells with no effect on eosinophils, precluding a major role for cyclooxygenase products. Sch 37224, an antileukotriene agent and an orally active novel antiallergy agent in sheep, guinea pigs, and humans, is as potent as betamethasone at blocking eosinophil infiltration, suggesting that it may also suppress human pulmonary inflammation.

Topics: Albumins; Anaphylaxis; Animals; Asthma; Azepines; Betamethasone; Bronchoalveolar Lavage Fluid; Cell Count; Eosinophils; Guinea Pigs; Histamine; Immunization; Indomethacin; Leukotriene Antagonists; Lipoxygenase Inhibitors; Lung; Male; Naphthyridines; Ovalbumin; Platelet Activating Factor; Pyrazoles; Thromboxanes; Triazoles

The effects of inhibitors of the cyclooxygenase and lipoxygenase pathways of arachidonic acid (AA) metabolism were studied on the contractions of guinea pig tracheal spirals and lung parenchymal strips induced by antigen and calcium ionophore A23187. Inhibition of the cyclooxygenase pathway with indomethacin results in enhancement of antigen- and A23187-induced contraction of trachea which is a result of diversion of AA into the lipoxygenase pathway and inhibition of modulatory cyclooxygenase products. Indomethacin does not enhance parenchymal contractions but partly inhibits contraction induced by a strong stimulus (5.7 microM A23187 or 100 micrograms/ml ovalbumin). Parenchymal contraction is inhibited by agents that block the lipoxygenase pathway of AA metabolism, phenidone and nordihydroguaiaretic acid. These agents inhibit the prolonged phase of antigen-induced tracheal contraction but in some cases enhance the early phase of tracheal contraction induced by antigen or A23187. The results suggest that contraction of parenchyma induced by antigen or A23187 are the result of a bronchoconstrictor lipoxygenase product and only have a cyclooxygenase bronchoconstrictor component following a strong stimulus. In contrast, contraction of trachea also appears to be the result of a bronchoconstrictor lipoxygenase product which may not be identical to that contracting parenchyma, and is modulated by cyclooxygenase products. The results emphasize the importance of comparing small and large airways to further our understanding of asthmatic broncho-constriction.

Topics: Airway Resistance; Animals; Anti-Bacterial Agents; Antigens; Arachidonic Acid; Arachidonic Acids; Calcimycin; Cyclooxygenase Inhibitors; Guinea Pigs; In Vitro Techniques; Lipoxygenase Inhibitors; Male; Ovalbumin; Pyrazoles; Trachea

Ovalbumin (OA) and the calcium ionophore A23187 induced a dose-dependent contraction of guinea pig tracheal strips. The OA-induced contraction (of sensitized trachea) consisted of an initial peak concentration, maximal between 5 and 10 min, followed by a very gradual decline from the peak. On the other hand, A23187 induced a sustained contraction of the trachea with a more gradual onset. Both antigen- and A23187-induced contractions required the presence of extracellular calcium. The response was not reduced by delaying (up to 10 min) the addition of calcium, suggesting that the mechanism of antigen-induced contraction differs from that of antigen-induced histamine secretion from rat mast cells and human basophils. The 1st min of the OA-induced contraction was inhibited significantly by mepyramine (10(-5) M) suggesting that histamine contributed to the contraction at this time point. In contrast, A23187-induced contraction was unaffected by mepyramine. On the other hand, both the A23187-induced contraction and the prolonged phase of the OA-induced contraction were enhanced by indomethacin, a cyclooxygenase inhibitor, and inhibited by phenidone, a cyclooxygenase-lipoxygenase inhibitor. This suggests that a product of the lipoxygenase pathway of arachidonic acid metabolism contributes to OA- and A23187-induced contraction of the guinea pig trachea.

Topics: Animals; Anti-Bacterial Agents; Antigens; Calcimycin; Calcium; Contracture; Guinea Pigs; Indomethacin; Male; Ovalbumin; Pyrazoles; Pyrilamine; Time Factors; Trachea

Enhancement of allergic tracheal constriction and contraction of the trachea by AA in the presence of cyclooxygenase inhibitors may reflect diversion of AA metabolism from the cyclooxygenase pathway.

Topics: Airway Resistance; Animals; Cyclooxygenase Inhibitors; Guinea Pigs; Hypersensitivity; Indomethacin; Lipoxygenase Inhibitors; Male; Meclofenamic Acid; ortho-Aminobenzoates; Ovalbumin; Prostaglandins E; Pyrazoles; Trachea