Effects of combined hyperoxia and cyclooxygenase inhibition in neonatal rat lungs.
We examined the hypothesis that persistent pulmonary hypertension of the newborn (PPHN) associated with ibuprofen is due to alterations in biochemical and molecular regulators of oxidative stress and NO signaling. Newborn rats breathing 50% O2 or room air from the first day of life (P1), received early IP injections of: 1) indomethacin (0.2 mg/kg) on P1 and 0.1 mg/kg on P2 and P3; 2) ibuprofen (10 mg/kg) on P1 and 5 mg/kg on P2 and P3; or 3) saline on P1, P2 and P3, then euthanized on P4; or late treatment on P4, P5 and P6, then euthanized on P7. Lung biomarkers for oxidative stress (8- epi-PGF2a), DNA damage (8-hydroxy-2'-deoxyguanosine) and pulmonary hypertension (ET-1, big ET-1, and total NO) were assessed. Despite timing of the dose and oxygen exposure, both drugs resulted in increased alveolar size. Both drugs had no beneficial effects on oxidative stress. Indomethacin treatment in O2 resulted in higher pulmonary levels of 8-epi-PGF2alpha which was associated with downregulation of most antioxidant genes with early treatment and overexpression of GPX5 and 6 with late treatment. Early and late ibuprofen treatment suppressed hyperoxia-induced NOx production and downregulated iNOS. Postponing treatment had no significant beneficial effects on biomolecular regulators of oxidative stress and NO signaling. The effect of ibuprofen on pulmonary NOx may explain in part, the transient PPHN seen in ibuprofen-treated preterm infants.
Kuniyoshi
Katherine M
KM
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of California Irvine, Irvine, CA.kmiyokok@yahoo.com
Brock
Romy S
RS
Gebrekristos
Bisrat H
BH
Abad-Santos
Matthew
M
Hoang
Dinh
D
Modanlou
Houchang D
HD
Willis
Brigham C
BC
Beharry
Kay D
KD