Sodium nitrite prevents impaired postnatal alveolar development

Abstract

Deficient nitric oxide (NO) signaling plays a critical role in the pathogenesis of bronchopulmonary dysplasia (BPD); however, clinical trials of inhaled NO (iNO) as a preventive therapy for BPD have shown little to no benefit. A biochemical obstacle to effective NO-based therapy relates to the high reactivity of NO, potentially leading to harmful oxidation and nitration. Hypothesizing that nitrite-based therapy has less potential to produce adverse reactions, we compared the preventive effects of sodium nitrite (NaNO₂) and iNO on lung morphology, NO content and signaling, S-nitrosothiols (SNOs), and tyrosine nitration in a novel rat model of experimental BPD. From postnatal days (PNDs) 1-21, rat pups were exposed to normoxia or to hyperoxia-intermittent hypoxia (H-IH; PND 1-7 85% O₂, PND 7-14 60% O₂, and PND 14-21 normoxia with intermittent exposure to 10% O₂ for 10 min every 4 h) while receiving daily subcutaneous (sc) NaNO₂ (20 mg/kg) or continuous iNO (10 ppm). Controls were treated with vehicle or were not exposed to iNO. Exposure to H-IH caused alveolar and pulmonary vascular hypoplasia, pulmonary hypertension (PH), decreased lung NO content and signaling, and increased tyrosine nitration. NaNO₂ prevented abnormal lung morphology and PH, normalized NO content and signaling, and prevented nitration. iNO prevented PH, but had minimal effects on abnormal distal airspace morphology, and caused nitration and alveolar hypoplasia in control (normoxia-exposed) animals. Treatment with NaNO₂ increased S-nitrosylation of nine lung proteins; none were increased by iNO. These observations provide a biological rationale for superior efficacy of NaNO₂ in preventing experimental BPD.NEW & NOTEWORTHY Deficient nitric oxide (NO) signaling plays a critical role in bronchopulmonary dysplasia (BPD); however, human trials of inhaled NO (iNO) to prevent BPD have shown little to no benefit. We compared preventive effects of sodium nitrite (NaNO₂) to iNO in a novel rat model of experimental BPD. NaNO₂ prevented impaired postnatal alveolarization, whereas iNO had minimal effect. NaNO₂ inhibited nitration and enhanced S-nitrosylation of several proteins in the lung, potentially explaining its superiority to iNO.

Keywords: 3-nitrotyrosine; S-nitrosylation; nitric oxide; serine-tRNA ligase; xanthine oxidoreductase.