Lipid mediators in oxygen-induced airway remodeling and hyperresponsiveness in newborn rats.
We examined whether lipid mediators have a causal role in neonatal hyperoxia-induced lung damage, specifically, airway remodeling and hyperresponsiveness. Newborn rat pups were exposed to hyperoxia (> 95% O2 from Days 4 to 14 and 65% from Days 14 to 32) or normoxia. The 5-lipoxygenase inhibitor, LTD4 receptor antagonist, and inhibitor of platelet-activating factor synthesis, Wy-50,295 (30 mg/kg), or vehicle was administered daily from Days 3 to 32. Oxygen exposure significantly increased (p < 0.05) the production of one potential lipid mediator group, peptido-LTs, from explanted lung slices and large airways from 2-wk-old rat pups. At 4 wk, only the large airway tissue output showed significant elevation because of oxygen exposure. At both ages, Wy-50,295 significantly decreased (p < 0.05) the production of peptido-LTs in the lung and large airways of oxygen-exposed pups. Pulmonary function and airway wall morphometry were studied in 5-wk-old rat pups 2 to 3 d after oxygen exposure and drug administration ceased. The resistance change in response to methacholine (0 to 20 microg/kg body weight given intravenously) was greater (p < 0.02) in oxygen-exposed animals. Oxygen exposure caused significant (60% increase) smooth muscle thickening (p < 0.05). Wy-50,295 prevented the oxygen-induced airway hyperresponsiveness and smooth muscle thickening. We conclude that chronic hyperoxic exposure causes an increase in pulmonary production of at least one lipid mediator, peptido-LTs, from newborn rats and that this is associated with airway smooth muscle layer thickening and, consequently, airway hyperresponsiveness.
Department of Physiology, Faculty of Medicine, the Perinatal Research Centre, University of Alberta, Edmonton, Canada.
J S
JS
Burghardt
V
V
Boros
D F
DF
Biggs
D M
DM
Olson
D000818:Animals; D000831:Animals, Newborn; D001980:Bronchi / Q000473:pathology / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D001985:Bronchial Provocation Tests; D001997:Bronchopulmonary Dysplasia / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007231:Infant, Newborn; D017997:Leukotriene C4 / Q000502:physiology*; D017998:Leukotriene D4 / Q000502:physiology*; D017999:Leukotriene E4 / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000473:pathology / Q000503:physiopathology; D009280:Naphthaleneacetic Acids / Q000494:pharmacology*; D010100:Oxygen / Q000009:adverse effects*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016859:Lipoxygenase Inhibitors; D009280:Naphthaleneacetic Acids; D011804:Quinolines; C067525:S(alpha)-methyl-6-(2-quinolinylmethoxy)-2-naphthaleneacetic acid; D017997:Leukotriene C4; D017998:Leukotriene D4; D017999:Leukotriene E4; D010100:Oxygen