Original Article Effects of hyperoxia and cyclooxygenase inhibition on neonatal rat lungs
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
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 Email: firstname.lastname@example.org Or: email@example.com