Arachidonic acid metabolites do not mediate toluene diisocyanate-induced airway hyperresponsiveness in guinea pigs.
Arachidonic acid metabolites have previously been demonstrated to mediate the airway hyperresponsiveness observed in guinea pigs and dogs after exposure to ozone. Guinea pigs were treated with indomethacin (a cyclooxygenase inhibitor), U-60,257 (piriprost, a 5-lipoxygenase inhibitor), or BW775c (a lipoxygenase and cyclooxygenase inhibitor) and exposed to air or 3 ppm TDI. Airway responsiveness to acetylcholine aerosol was examined 2 h after exposure. In control animals, the provocative concentration of acetylcholine which caused a 200% increase in pulmonary resistance over baseline (PC200) was significantly less (p less than 0.05) after exposure to TDI (8.6 +/- 2.0 mg/ml, geometric mean + geometric SE, n = 10) than after exposure to air (23.9 + 2.5 mg/ml, n = 14). The airway responsiveness to acetylcholine in animals treated with indomethacin or piriprost and exposed to TDI was not different from that of control animals exposed to TDI. Treatment with BW755c enhanced the airway hyperresponsiveness observed in animals exposed to TDI without altering the PC200 of animals exposed to air. The PC200 of animals treated with BW755c and exposed to TDI (2.3 + 0.8 mg/ml, n = 8) was significantly lower than the PC200 of control animals exposed to TDI (p less than 0.025). These results suggest that products of arachidonic acid metabolism are not responsible for TDI-induced airway hyperresponsiveness in guinea pigs. BW755c, however, appears to potentiate the TDI-induced airway hyperresponsiveness to acetylcholine by an as yet unidentified mechanism.
Gordon
T
T
Department of Medicine, Northern California Occupational Health Center, University of California, San Francisco 94110.
Thompson
J E
JE
Sheppard
D
D
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000109:Acetylcholine / Q000494:pharmacology; D000402:Airway Obstruction / Q000139:chemically induced; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors; D004285:Dogs; D004357:Drug Synergism; D011464:Epoprostenol / Q000494:pharmacology / Q000031:analogs & derivatives; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D010126:Ozone; D011720:Pyrazoles / Q000494:pharmacology; D012137:Respiratory System / Q000187:drug effects*; D014051:Toluene 2,4-Diisocyanate
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D014051:Toluene 2,4-Diisocyanate; D016718:Arachidonic Acid; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D010126:Ozone; D011464:Epoprostenol; D000109:Acetylcholine; C035296:piriprost; D007213:Indomethacin