Cysteinyl leukotrienes do not mediate lipopolysaccharide-induced airway hyperresponsiveness in guinea pigs.
Inhalation of bacterial lipopolysaccharide (LPS) by guinea pigs caused bronchial hyperreactivity to acetylcholine with a peak at 2 hr after exposure. Exposure to 0.01% LPS for 30 min resulted in an elevation of cysteinyl leukotrienes (cys-LTs) content in bronchoalveolar lavage fluid (BALF) which was obtained 1 hr after LPS exposure. The cys-LTs antagonist, ONO-1078 (10 mg/kg, p.o.), significantly inhibited LPS-induced bronchial hyperreactivity, but ICI-204,219 (10 mg/kg, p.o.), another cys-LT antagonist, did not. Each dose employed in the present study was sufficient to inhibit LTD4-induced broncho-constriction in guinea pigs. In order to investigate the inhibitory mechanism of ONO-1078, the effect on the LPS-induced production of tumor necrosis factor (TNF) was examined. The amount of TNF in BALF increased significantly 2 hr after exposure to LPS. The inhalation of murine recombinant TNF-alpha (5 x 10(4) u/ml) resulted in bronchial hyperreactivity in guinea pigs. ONO-1078 (10 mg/kg, p.o.) inhibited the increase of LPS-induced TNF in BALF, but ICI-204,219 (10 mg/kg, p.o.) had no effect. These results suggest that TNF plays an important role in the onset of LPS-induced bronchial hyper-reactivity, and that ONO-1078 inhibits the LPS-induced airway hyperreactivity probably due to the inhibition of TNF production.
Uno
T
T
Department of Pharmacology, Gifu Pharmaceutical University, Japan.
Tanaka
H
H
Nagai
H
H
D000109:Acetylcholine / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry* / Q000166:cytology; D002867:Chromones / Q000494:pharmacology; D006168:Guinea Pigs; D007211:Indoles; D015289:Leukotrienes / Q000032:analysis / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009504:Neutrophils / Q000502:physiology; D048448:Phenylcarbamates; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D013189:SRS-A / Q000037:antagonists & inhibitors; D013449:Sulfonamides; D013997:Time Factors; D014105:Tosyl Compounds / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology
D018927:Anti-Asthmatic Agents; D002867:Chromones; D007211:Indoles; D015289:Leukotrienes; D008070:Lipopolysaccharides; D048448:Phenylcarbamates; D013189:SRS-A; D013449:Sulfonamides; D014105:Tosyl Compounds; D014409:Tumor Necrosis Factor-alpha; D000109:Acetylcholine; C047681:pranlukast; C062735:zafirlukast