Am. J. Respir. Crit. Care Med., Vol 154, No. 4, 10 1996, 837-842.
Lipid mediators in oxygen-induced airway remodeling and hyperresponsiveness in newborn rats
JS Burghardt, V Boros, DF Biggs and DM Olson
Department of Physiology, Faculty of Medicine, the Perinatal Research Centre, University of Alberta, Edmonton, Canada.
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.
