Inhibition of the 5-lipoxygenase pathway with piriprost (U-60,257)_protects normal primates from ozone-induced methacholine hyperresponsive small airways

• Published in: Prostaglandins Vol. 35; no. 3; pp. 459 - 466
• Main Authors: Johnson, Herbert G., Stout, Barbara K., Ruppel, Patty L.
• Format: Journal Article
• Language: English
• Published: Stoneham, MA Elsevier Inc 01.03.1988; Butterworth-Heinemann
• Subjects: Airway Resistance - drug effects; Animals; Arachidonate Lipoxygenases - antagonists & inhibitors; Biological and medical sciences; Bronchi - physiopathology; Bronchial Diseases - chemically induced; Bronchial Diseases - physiopathology; Epoprostenol - pharmacology; Female; Lipoxygenase Inhibitors; Lung Compliance - drug effects; Macaca mulatta; Medical sciences; Methacholine Chloride; Methacholine Compounds - pharmacology; Ozone - toxicity; Pharmacology. Drug treatments
• ISSN: 0090-6980
• DOI: 10.1016/0090-6980(88)90136-0

Weekly exposure to ozone in seven normal Rhesus monkeys led to induction of methacholine hypersensitive airways (R L increases 242 ± 60% and C dyn decreases 68 ± 13% of baseline methacholine responses). It took 19 weeks to establish this hyperresponse that persisted for > 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 C dyn measurement (C dyn% 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 R L and C dyn (R L% changed 151 ± 41 vs 31.1 ± 49, P = 0.03, and for C dyn 62.7 ± 8 vs 10, P = 0.0006, placebo and piriprost, respectively). We conclude that 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 an alveiolitis).