Mechanisms contributing to ozone-induced bronchial hyperreactivity in guinea-pigs.
The effect of ozone (3 ppm, 15-120 min) on bronchial reactivity in the guinea-pig was studied. Ozone induced marked (6-250-fold) bronchial hyperreactivity (BHR) to a range of inhaled, but not intravenous bronchoconstrictors. The degree of BHR was related to the duration of prior ozone exposure. The glutathione redox status was shifted to a more oxidized state in lung after 120 min ozone treatment, although no changes were found in the energy status of lung tissue, as judged by the concentrations of adenosine phosphates. Ascorbic acid pretreatment prevented BHR induced by 30 min ozone exposure. Neutral endopeptidase inhibitors elicited BHR to both substance P and histamine, but did not further enhance bronchoconstriction to substance P after ozone exposure for 120 min. Neither mepyramine, fentanyl, indomethacin nor a 5-lipoxygenase inhibitor (BW B70C), given prior to ozone exposure prevented the induction of BHR to histamine. Atropine or bilateral vagotomy reduced BHR after a 120-min, but not 30-min exposure to ozone. We conclude that in the guinea-pig, ozone induces non-specific, route-dependent BHR by oxidative injury, reducing airway NEP activity and enhancing the cholinergic and peptidergic component to bronchoconstriction. Neither cyclooxygenase nor 5-lipoxygenase products appear to play a role in ozone-induced BHR in this animal model.
Yeadon
M
M
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, UK.
Wilkinson
D
D
Darley-Usmar
V
V
O'Leary
V J
VJ
Payne
A N
AN
D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced*; D016084:Bronchoconstriction / Q000187:drug effects*; D004195:Disease Models, Animal; D005283:Fentanyl / Q000008:administration & dosage / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000494:pharmacology; D010084:Oxidation-Reduction; D010126:Ozone / Q000008:administration & dosage / Q000633:toxicity*; D011738:Pyrilamine / Q000008:administration & dosage / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology; D014630:Vagus Nerve / Q000502:physiology
D000227:Adenine Nucleotides; D016859:Lipoxygenase Inhibitors; D009842:Oligopeptides; D013373:Substance P; D010126:Ozone; D001285:Atropine; D006632:Histamine; C055303:BW 443C; D015260:Neprilysin; D005978:Glutathione; D011738:Pyrilamine; D001205:Ascorbic Acid; D005283:Fentanyl; D007213:Indomethacin