Effects of indomethacin and ibuprofen on lung morphometry and biomarkers for oxidative stress, dna damage and persistent pulmonary hypertension of the newborn in neonatal rats

Background: Indomethacin has been the drug of choice for the treatment of symptomatic patent ductus arteriosus; however, its use is associated with renal and gastrointestinal adverse effects. Although ibuprofen lysine has been shown to be a safer alternative to indomethacin, it was demonstrated to result in persistent pulmonary hypertension of the newborn (PPHN). Objective: To compare the effects of indomethacin and ibuprofen on morphology and biomarkers for oxidative stress, DNA damage and PPHN in normoxic and hyperoxic rat lungs. Methods: Newborn rats were treated with room air (RA) or hyperoxia (50% O2) from the first day of life (P1). The rat pups received intraperitoneal injections of either indomethacin (0.2 mg/kg) on P1 and 0.1 mg/kg on P2 and P3; ibuprofen (10 mg/kg) on P1 and 5 mg/kg on P2 and P3; or saline on P1, P2 and P3, then were killed on P4. Lung morphometry and biomarkers for oxidative stress (8-epi-PGF2α), DNA damage (8-hydroxy-2′-deoxyguanosine) and PPHN (endothelin 1 (ET-1), big ET-1 and total nitric oxide (NO)) were assessed. Results: Both drugs produced oversimplified alveoli with dilated alveolar ducts, but the effect was more severe and widespread with indomethacin. Changes in lung morphometry with indomethacin were associated with higher 8-epi-PGF2α (reflecting oxidative stress) and total NO during hyperoxia; and higher ET-1 during RA. Both drugs suppressed 8-hydroxy-2′-deoxyguanosine (reflecting DNA damage) during hyperoxia. Conclusions: These data demonstrate that both drugs adversely affect lung morphometry. Although the effects were less severe with ibuprofen than indomethacin, treatment with both drugs may lead to PPHN and impaired alveolar and pulmonary vascular development.