Inhaled nitric oxide improves lung structure and pulmonary hypertension in a model of bleomycin-induced bronchopulmonary dysplasia in neonatal rats

Abstract

Tourneux P, Markham N, Seedorf G, Balasubramaniam V, Abman SH. Inhaled nitric oxide improves lung structure and pulmonary hypertension in a model of bleomycin-induced bronchopulmonary dysplasia in neonatal rats. Am J Physiol Lung Cell Mol Physiol 297: L1103-L1111, 2009. First published October 16, 2009 doi:10.1152/ajplung.00293.2009.-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 Bleoinduced 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 Ͻ 0.01) and wall thickness (P Ͻ 0.01) and restored vessel density after Bleo (P Ͻ 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. lung development; nitric oxide; alveolarization BRONCHOPULMONARY DYSPLASIA (BPD) is the chronic lung disease of infancy that most commonly occurs in premature infants who require mechanical ventilation and oxygen therapy for acute respiratory distress, but it also occurs in immature infants with few signs of initial disease (25). BPD has a multifactorial etiology, including oxygen toxicity (40), preterm delivery (53), hypoxia or hyperoxia (32, 50), infection, and inflammation (25). Perinatal inflammation can result from diverse mechanisms, including chorioamnionitis, hyperoxia, infection, or ventilator-induced lung injury, and it is strongly related to the development of BPD in various animal models, as well as in the clinical setting (8,29,37,59).Histologically, BPD is characterized by disruption of alveolar and vascular growth after preterm birth. The saccular and alveolar periods of lung development are characterized by rapid increases in vessel growth and septation of the distal air space. These periods of lung development occur from the 24th wk of gestation through the first 3 yr of life in humans and during the first 3 wk of ...

Leukotriene B4mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury

“…In neonatal rats, our laboratory and others have reported that repeated systemic administration of bleomycin leads to a selective decrease in lung growth, along with arrested alveolarization, vascular hypoplasia, and chronic PHT (15,30,44,52), similar to the lung pathology observed in human infants with severe BPD. We have employed this model to demonstrate a critical role for macrophage influx and macrophagederived tumor necrosis factor (TNF)-␣ in the pathogenesis of chronic PHT (26,44).…”

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

“…Previous studies from our group have established a model of repeated systemic bleomycin injection in neonatal rats that results in lung injury mimicking characteristics typical of BPD. This model is a useful tool to help understand mechanisms contributing to lung development and remodeling (31) but also to study the effects of therapeutic interventions aimed at preventing lung parenchymal and vascular injury (31,50,56).The chemotherapeutic agent bleomycin sulfate causes a pulmonary inflammatory and fibrotic response in rodents when instilled as a single intratracheal dose (27) or by repeated intraperitoneal injection (3). Bleomycin-induced lung injury is characterized by induction of proinflammatory cytokines (18), influx of macrophages and other inflammatory cells (23), "emphysematous" lung morphology, and severe PHT (49, 60).…”

“…Previous studies from our group have established a model of repeated systemic bleomycin injection in neonatal rats that results in lung injury mimicking characteristics typical of BPD. This model is a useful tool to help understand mechanisms contributing to lung development and remodeling (31) but also to study the effects of therapeutic interventions aimed at preventing lung parenchymal and vascular injury (31,50,56).…”

Insights into etiological factors of pulmonary hypertension in cancer patients

“…Bleomycin has been suggested as the main factor in causing pulmonary veno-occlusive disease in a reported series of patients [63,64]. Bleomycin has long track of being used in experimental studies to induce idiopathic pulmonary fibrosis and pulmonary hypertension [65][66][67][68]. Management usually directed toward supportive treatment, steroids and azathioprine with a possible role for imatinib and bosentan [69][70][71].…”