AJTR Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Am J Translational Res 2010;2(3):332-344

Original Article
Effects of hyperoxia and cyclooxygenase inhibition on neonatal rat

Katherine M. Kuniyoshi, Romy S. Brock, Bisrat H. Gebrekristos, Matthew Abad-Santos, Dinh Hoang, Houchang D.
Modanlou, Brigham C. Willis, Kay D. Beharry

Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of California Irvine, Irvine, CA ;
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Miller Children’s Hospital, Long Beach, CA
and Department of Pediatrics, University of Arizona, Phoenix, AZ.

Received February 8, 2010; accepted March, 2010; available online March, 2010

Abstract: 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 morphology, and biomarkers for oxidative stress (8-epi-PGF2), 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 air space. While both drugs
decreased hyperoxia-induced pulmonary hemorrhage, they had no beneficial effects on oxidative stress.
Indomethacin treatment resulted in higher pulmonary levels of 8-epi-PGF2α which was associated with
decreased GPX2 gene expression with early treatment and overexpression of GPX7 with late treatment.  Early and
late ibuprofen treatment suppressed hyperoxia-induced NOx production.  Postponing treatment had no significant
beneficial effects on lung architecture or biomolecular regulators of oxidative stress and NO signaling.  The effect
of ibuprofen on pulmonary NOx may explain in part, the transient PPHN seen ibuprofen-treated preterm infants.  
The effect of both drugs on the lung architecture implicates prostaglandins in alveolar development may
contribute to the drugs efficacy for PDA closure. (AJTR1002002).

Key words: Antioxidants, DNA damage, endothelins, nitric oxide, oxidative stress

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Address all correspondence to:
Katherine M. Kuniyoshi, MD
Department of Pediatrics/Division of Neonatology
University of California, Irvine
101 The City Drive South
Route 81, Building #56, Suite 600
Orange, CA 92868                                
Tel: (714) 456-6933
FAX: (714) 456-7658
Or: kbeharry@uci.edu