piriprost and Disease-Models--Animal

Topics: Animals; Asthma; Disease Models, Animal; Dogs; Epoprostenol; Guinea Pigs; Haplorhini; Humans; Neutrophils; SRS-A

It is known that reactive oxygen species cause lung injury in association with activation of arachidonate metabolism. Because metabolites of the cyclooxygenase pathway do not appear to mediate the injury, we considered that the 5-lipoxygenase pathway might be activated and that inhibition of the pathway could interfere with the development of the injury. Thus, we sought to induce an oxidant lung injury and to prevent such injury by inhibiting lipoxygenase pathway or by blocking leukotriene action. In isolated rat lungs, glucose oxidase added to a glucose-containing, cell-free perfusate was used to produce the injurious oxygen species. Lung edema occurred and increased with increasing oxygen tension in the inspired air. Light microscopy of the lung showed perivascular fluid cuffs, and electron microscopy showed endothelial cell damage. Measurements in the lung effluent showed that concentrations of 5-hydroxyeicosatetraenoic acid (5-HETE) and of cyclooxygenase metabolites increased after glucose oxidase administration; BW 755C, U60,257, and FPL 55712 inhibited the glucose-oxidase-induced lung edema. And U60,257 also inhibited the glucose-oxidase-induced increase in 5-HETE without concomitant inhibition of cyclooxygenase metabolites. Thus, glucose oxidase via generation of active oxygen species stimulated the lung 5-lipoxygenase pathway, and inhibitors of 5-lipoxygenase protected against the oxidant lung injury. Further, in these experiments, the injury occurred in the absence of circulating blood cells and was augmented by increasing the inspired oxygen concentration.

Topics: Animals; Biological Assay; Catalase; Cyclooxygenase Inhibitors; Disease Models, Animal; Enzyme Inhibitors; Epoprostenol; Glucose Oxidase; Guinea Pigs; Hydrogen Peroxide; Hydroxyeicosatetraenoic Acids; Ileum; Indomethacin; Lipoxygenase; Lung; Lung Injury; Male; Pulmonary Edema; Rats; Rats, Inbred Strains

Piriprost (U-60,257), a selective inhibitor of the 5-lipoxygenase, inhibited bronchoconstriction in a modification of the Konzett-Rossler procedure in which bronchoconstriction in sensitized guinea pigs may reflect leukotriene production. The duration of action of this compound and also the possible development of tachyphylaxis to its action upon repeated dosing were studied using a newly developed procedure for dosing conscious animals via the aerosol route. Duration of action with the lowest concentration which afforded maximum protection (180 s exposure to a 0.01% solution) was approximately 1.5 h. No decrease in drug potency was observed after 7 daily drug treatments.

Topics: Administration, Oral; Allergens; Animals; Asthma; Bronchial Spasm; Bronchodilator Agents; Disease Models, Animal; Drug Administration Schedule; Epoprostenol; Guinea Pigs; Lipoxygenase Inhibitors; SRS-A; Time Factors