Inhaled nitric oxide improves lung structure and pulmonary hypertension in a model of bleomycin-induced bronchopulmonary dysplasia in neonatal rats.
Whether inhaled nitric oxide (iNO) prevents the development of bronchopulmonary dysplasia (BPD) in premature infants is controversial. In adult rats, bleomycin (Bleo) induces lung fibrosis and pulmonary hypertension, but the effects of Bleo on the developing lung and iNO treatment on Bleo-induced neonatal lung injury are uncertain. Therefore, we sought to determine whether early and prolonged iNO therapy attenuates changes of pulmonary vascular and alveolar structure in a model of BPD induced by Bleo treatment of neonatal rats. Sprague-Dawley rat pups were treated with Bleo (1 mg/kg ip daily) or vehicle (controls) from day 2 to 10, followed by recovery from day 11 to 19. Treatment groups received early (days 2-10), late (days 11-19), or prolonged iNO therapy (10 ppm; days 2-19). We found that compared with controls, Bleo increased right ventricular hypertrophy (RVH), and pulmonary arterial wall thickness, and reduced vessel density alveolarization. In each iNO treatment group, iNO decreased RVH (P < 0.01) and wall thickness (P < 0.01) and restored vessel density after Bleo (P < 0.05). iNO therapy improved alveolarization for each treatment group after Bleo; however, the values remained abnormal compared with controls. Prolonged iNO treatment had greater effects on lung structure after bleomycin than late treatment alone. We conclude that Bleo induces lung structural changes that mimic BPD in neonatal rats, and that early and prolonged iNO therapy prevents right ventricle hypertrophy and pulmonary vascular remodeling and partially improves lung structure.
Tourneux
Pierre
P
Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Aurora, USA. tourneux.pierre@chu-amiens.fr
Markham
Neil
N
Seedorf
Gregory
G
Balasubramaniam
Vivek
V
Abman
Steven H
SH
D000280:Administration, Inhalation; D000818:Animals; D000831:Animals, Newborn; D001761:Bleomycin; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000201:enzymology / Q000473:pathology*; D017380:Hypertrophy, Right Ventricular / Q000150:complications / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D055370:Lung Injury / Q000139:chemically induced / Q000150:complications* / Q000201:enzymology / Q000473:pathology*; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D001761:Bleomycin; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D040301:Vascular Endothelial Growth Factor Receptor-2