Inhibition of the 5-lipoxygenase pathway with piriprost (U-60,257) protects normal primates from ozone-induced methacholine hyperresponsive small airways.
Weekly exposure to ozone in seven normal Rhesus monkeys led to induction of methacholine hypersensitive airways (RL increases 242 +/- 60% and Cdyn decreases 68 +/- 13% of baseline methacholine responses). It took 19 weeks to establish this hyperresponse that persisted for greater than 15 weeks once ozone was stopped. A second exposure led to similar response peaks in 6 weeks. At the peak of the second response, weekly 1% piriprost exposure before ozone led to a return to baseline that was not different between placebo and piriprost treated animals (9.4 +/- 1.0 and 4.3 +/- 2.9 weeks, placebo and treated, respectively P = 0.09 NS). A statistical difference in the mecholyl response in placebo and piriprost treated groups while on ozone was shown only in the Cdyn measurement (Cdyn% change 68 +/- 13 vs 24 +/- 14, placebo and piriprost, respectively P = 0.03). Off ozone (or return to baseline), a statistical difference could be detected both in RL and Cdyn (RL% changed 151 +/- 41 vs 31.1 +/- 49, P = 0.03, and for Cdyn 62.7 +/- 8 vs 9 +/- 10, P = 0.0006, placebo and piriprost, respectively). We conclude tha the primate provides a chronic model of airways reactivity in which the role of lipoxygenase is implicated because of the beneficial role of piriprost, and further that the ozone lesion is primarily in the smaller airways (possibly and alveolitis).
Johnson
H G
HG
Hypersensitivity Disease Research, Upjohn Company, Kalamazoo, MI 49001.
Stout
B K
BK
Ruppel
P L
PL
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001980:Bronchi / Q000503:physiopathology*; D001982:Bronchial Diseases / Q000139:chemically induced / Q000503:physiopathology*; D011464:Epoprostenol / Q000494:pharmacology* / Q000031:analogs & derivatives; D005260:Female; D016859:Lipoxygenase Inhibitors; D008170:Lung Compliance / Q000187:drug effects; D008253:Macaca mulatta; D016210:Methacholine Chloride; D008688:Methacholine Compounds / Q000494:pharmacology*; D010126:Ozone / Q000633:toxicity*
D016859:Lipoxygenase Inhibitors; D008688:Methacholine Compounds; D016210:Methacholine Chloride; D010126:Ozone; D011464:Epoprostenol; D001091:Arachidonate Lipoxygenases; C035296:piriprost