semaxinib and Bronchopulmonary-Dysplasia

Topics: Angiogenesis Inhibitors; Bronchopulmonary Dysplasia; Endothelial Growth Factors; Gene Expression Regulation, Developmental; Humans; Indoles; Infant, Newborn; Lymphokines; Proto-Oncogene Proteins; Pyrroles; Receptor Protein-Tyrosine Kinases; Respiration, Artificial; Respiratory Distress Syndrome, Newborn; Risk Factors; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature neonates. Classical BPD is caused by hyperoxia and high-pressure mechanical ventilation, whereas BPD in recent era is caused by impaired pulmonary angiogenesis and alveolarization in extreme prematurity. Although sildenafil was reported to be effective in a hyperoxia-induced rat BPD model, several clinical trials could not demonstrate any significant improvement in the respiratory statuses of BPD infants. Riociguat is a soluble guanylate cyclase stimulator that increases cyclic guanosine monophosphate activity in a nitric oxide independent manner. However, a beneficial effect in BPD has not been established yet.. We established BPD model in rats by injection of SU5416 on day 1 followed by maintenance under normoxia, which resulted in oversimplified alveoli, sparse pulmonary capillary vessels, severe pulmonary hypertension, and growth retardation, which mimicked the features observed in recent clinical management of BPD. We administered riociguat from day 10, when BPD rats exhibited growth retardation. Histological analyses demonstrated that riociguat treatment significantly but partially ameliorated lung alveolarization, vascularization, and pulmonary hypertension. However, the survival rate was not significantly improved by riociguat treatment.. Riociguat could ameliorate pulmonary alveolarization, vascularization, and hypertension in the SU5416 induced BPD rat model, but could not improve the overall survival.

Topics: Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Disease Models, Animal; Humans; Hyperoxia; Indoles; Infant, Newborn; Lung; Models, Theoretical; Pyrazoles; Pyrimidines; Pyrroles; Rats

VEGF plays a critical role during lung development and is decreased in human infants with bronchopulmonary dysplasia. Inhibition of VEGF receptors in the newborn rat decreases vascular growth and alveolarization and causes pulmonary hypertension (PH). Nitric oxide (NO) is a downstream mediator of VEGF, but whether the effects of impaired VEGF signaling are due to decreased NO production is unknown. Therefore, we sought to determine whether impaired VEGF signaling downregulates endothelial NO synthase (eNOS) expression in the developing lung and whether inhaled NO (iNO) decreases PH and improves lung growth after VEGF inhibition. Newborn rats received a single dose of SU-5416 (a VEGF receptor inhibitor) or vehicle by subcutaneous injection and were killed up to 3 wk of age for assessments of right ventricular hypertrophy (RVH), radial alveolar counts (RAC), lung eNOS protein, and NOx production in isolated perfused lungs (IPL). Neonatal treatment with SU-5416 increased RVH in infant rats and reduced RAC. Compared with controls, SU-5416 reduced lung eNOS protein expression by 89% at 5 days (P < 0.01). IPL studies from day 14 rats demonstrated increased baseline pulmonary artery pressure and lower perfusate NOx concentration after SU-5416 treatment. Importantly, iNO treatment prevented the increase in RVH and improved RAC after SU-5416 treatment. We conclude that treatment of neonatal rats with SU-5416 downregulates lung eNOS expression and that iNO therapy decreases PH and improves lung growth after SU-5416 treatment. We speculate that decreased NO production contributes to PH and decreases distal lung growth caused by impaired VEGF signaling.

Topics: Administration, Inhalation; Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Enzyme Inhibitors; Female; Humans; Hypertension, Pulmonary; Indoles; Infant, Newborn; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Pregnancy; Pulmonary Alveoli; Pyrroles; Rats; Receptors, Vascular Endothelial Growth Factor