Kathrine L. Daniel, Chantal Gaudet, Ali Hamraghani, Nadya Ben Fadel, Behzad Yeganeh, Robert P. Jankov
Children’s Hospital of Eastern Ontario Research Institute. University of Ottawa.
Canada
American Journal of Physiology Lung Cellular and Molecular Physiology
Am J Physiol Lung Cell Mol Physiol 2025;
DOI: 10.1152/ajplung.00324.2024
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 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 (PND) 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 s.c. 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.
Category
Class III. Pulmonary Hypertension Associated with Lung Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Medical Therapy. Efficacy or Lack of Efficacy
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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