5-hydroxy-6-8-11-14-eicosatetraenoic-acid and Pleurisy

Topics: Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Arachidonic Acids; Cell Count; Cyclooxygenase Inhibitors; Eicosanoids; Hydroxyeicosatetraenoic Acids; L-Lactate Dehydrogenase; Leukotriene B4; Lipoxygenase Inhibitors; Macrophages; Male; Neutrophils; Pleura; Pleurisy; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred Strains

CGS 8515 inhibited 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotriene B4 synthesis in guinea pig leukocytes (IC50 = 0.1 microM). The compound did not appreciably affect cyclooxygenase (sheep seminal vesicles), 12-lipoxygenase (human platelets), 15-lipoxygenase (human leukocytes) and thromboxane synthetase (human platelets) at concentrations up to 100 microM. CGS 8515 inhibited A23187-induced formation of leukotriene products in whole blood (IC50 values of 0.8 and 4 microM, respectively, for human and rat) and in isolated rat lung (IC50 less than 1 microM) in vitro. The selectivity of the compound as a 5-lipoxygenase inhibitor was confirmed in rat whole blood by the 20-70-fold separation of inhibitory effects on the formation of leukotriene from prostaglandin products. Ex vivo and in vivo studies with rats showed that CGS 8515, at an oral dose of 2-50 mg/kg, significantly inhibited A23187-induced production of leukotrienes in whole blood and in the lung. The effect persisted for at least 6 h in the ex vivo whole blood model. CGS 8515, at oral doses as low as 5 mg/kg, significantly suppressed exudate volume and leukocyte migration in the carrageenan-induced pleurisy and sponge models in the rat. Inhibitory effects of the compound on inflammatory responses and leukotriene production in leukocytes and target organs are important parameters suggestive of its therapeutic potential in asthma, psoriasis and inflammatory conditions.

Topics: Animals; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Benzoquinones; Biotransformation; Blood Platelets; Calcimycin; Dexamethasone; Guinea Pigs; Humans; Hydroxyeicosatetraenoic Acids; Indomethacin; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Male; Naphthoquinones; ortho-Aminobenzoates; Pleurisy; Quinones; Rats; Rats, Inbred Strains; Sheep

In studies of the role of leukotrienes in inflammatory reactions, the induction of rat reversed passive Arthus pleurisy (a type III allergic reaction) was employed. Increases of exudate volume, vascular permeability, and migration of inflammatory cells in the pleural cavity were observed. The vascular permeability was enhanced biphasically during 0-30 min (early response) and during 3-6 h (late response) after induction of the pleurisy. The infiltration of inflammatory cells, mainly polymorphonuclear leukocytes, into the cavity increased and reached a maximum 6 h after the pleurisy was induced. Leukotriene B4 (LTB4), 5-monohydroxyeicosatetraenoic acid (5-HETE), and slow-reacting substance of anaphylaxis (SRS-A), consisting of LTC4, LTD4 and LTE4, were detected in the exudate by reversed-phase high-performance liquid chromatography during the early response. The contents of LTC4 reached a maximum 10 min after the challenge, followed by a rapid decrease within 1 h. The rise and decay of LTC4 correlated with the increase in vascular permeability during the early phase. AA-861, a 5-lipoxygenase inhibitor, given intrapleurally inhibited the increase in vascular permeability, cell migration, and generation of leukotrienes during the early phase of the pleurisy. These results indicate that products of the 5-lipoxygenase pathway, such as LTC4 and LTB4, may play an important role as chemical mediators in the inflammatory reaction.

Topics: Animals; Arachidonate Lipoxygenases; Arthus Reaction; Benzoquinones; Biological Assay; Capillary Permeability; Chemotaxis, Leukocyte; Eosinophils; Female; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice; Monocytes; Neutrophils; Pleurisy; Pyrilamine; Quinones; Rabbits; Rats; SRS-A

AA-861, a selective 5-lipoxygenase inhibitor, suppressed A23187-induced formations of 5-HETE and LTB4 in rat peritoneal macrophages. Immunologically-stimulated generation of SRS-A was also inhibited in guinea pig lung and rat peritoneal cavity. AA-861 had no effects on histamine release from rat mast cells or passive cutaneous anaphylaxis in rats. Essentially no antagonistic activity to LTD4 or histamine was observed. This compound exerted an obvious inhibition of allergic bronchoconstriction in guinea pigs and a moderate reduction of carrageenin-induced paw edema and pleurisy in rats. These findings suggest that SRS-A plays an important role in asthmatic and inflammatory reactions.

Topics: Animals; Arachidonate Lipoxygenases; Asthma; Benzoquinones; Edema; Female; Guinea Pigs; Histamine Release; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase Inhibitors; Lung; Macrophages; Male; Mast Cells; Passive Cutaneous Anaphylaxis; Pleurisy; Quinones; Rats; Rats, Inbred Strains; SRS-A