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.
Burghardt
J S
JS
Department of Physiology, Faculty of Medicine, the Perinatal Research Centre, University of Alberta, Edmonton, Canada.
Boros
V
V
Biggs
D F
DF
Olson
D M
DM
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