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Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
Published on: October 19, 2013
Effects of combined hyperoxia and cyclooxygenase inhibition in neonatal rat lungs
Katherine M Kuniyoshi1, Romy S Brock, Bisrat H Gebrekristos
1Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of California Irvine, Irvine, CA.kmiyokok@yahoo.com
Insights
Ibuprofen and indomethacin treatments in newborn rats did not improve oxidative stress markers. Ibuprofen suppressed nitric oxide production, potentially explaining transient pulmonary hypertension in preterm infants.
Area of Science:
- Neonatal physiology
- Pharmacology
- Biochemistry
Background:
- Persistent pulmonary hypertension of the newborn (PPHN) is a critical condition in preterm infants.
- Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen are sometimes associated with PPHN.
- The underlying mechanisms, particularly involving oxidative stress and nitric oxide (NO) signaling, require further investigation.
Purpose of the Study:
- To investigate the hypothesis that NSAID-induced PPHN is linked to altered oxidative stress and NO signaling pathways.
- To compare the effects of early versus late administration of indomethacin and ibuprofen on neonatal lung development and related biomarkers.
Main Methods:
- Newborn rats were exposed to hyperoxia (50% O2) or room air.
- Animals received early or late intraperitoneal injections of indomethacin, ibuprofen, or saline.
- Lung tissue was analyzed for biomarkers of oxidative stress (8-epi-PGF2a), DNA damage (8-hydroxy-2'-deoxyguanosine), and pulmonary hypertension (ET-1, big ET-1, NO).
Main Results:
- Both indomethacin and ibuprofen increased alveolar size, irrespective of treatment timing or oxygen exposure.
- Neither drug demonstrated beneficial effects on oxidative stress markers.
- Indomethacin in hyperoxia increased pulmonary 8-epi-PGF2alpha, with differential effects on antioxidant genes based on treatment timing.
- Ibuprofen suppressed hyperoxia-induced NOx production and downregulated inducible nitric oxide synthase (iNOS).
Conclusions:
- NSAID treatment in neonatal rats did not mitigate oxidative stress.
- Ibuprofen's suppression of pulmonary NOx production may contribute to the transient PPHN observed in treated preterm infants.
- Treatment timing did not significantly alter the biomolecular effects on oxidative stress and NO signaling.
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 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.