Consecutive Daily Administration of Intratracheal Surfactant and Human Mesenchymal Stem Cells Attenuates Hyperoxia-induced Lung Injury in Neonatal Rats
Abstract Background: Surfactant therapy is a standard of care for preterm infants with respiratory distress and reduces the incidence of death and bronchopulmonary dysplasia in these patients. Mesenchymal stem cells (MSCs) attenuated hyperoxia-induced lung injury. Surfactant reduced the in vitro viability of human MSCs, and the combination therapy of surfactant and MSCs did not have additive effects on hyperoxia-induced lung injury in neonatal rats. The effects of 2 consecutive days of intratracheal administration of surfactant and MSCs on hyperoxia-induced lung injury were undetermined. Methods: Neonatal Sprague Dawley rats were reared in either room air (RA) or hyperoxia (85% O2) from postnatal days 1 to 14. On postnatal day 4, the rats received intratracheal injections of either 20 μL of normal saline (NS) or 20 μL of surfactant. On postnatal day 5, the rats reared in RA received intratracheal NS, and the rats reared in O2 received intratracheal NS or human MSCs (3 × 104 or 3 × 105 cells). Six study groups were examined: RA + NS + NS, RA + surfactant + NS, O2 + NS + NS, O2 + surfactant + NS, O2 + surfactant + MSCs (3 × 104 cells), and O2 + surfactant + MSCs (3 × 105 cells). The lungs were excised for analysis on postnatal day 14.Results: The rats reared in hyperoxia and treated with NS yielded significantly higher mean linear intercepts (MLIs) and cytokine levels and significantly lower vascular endothelial growth factors (VEGFs), platelet-derived growth factor protein expression, and vascular density than did those reared in RA and treated with NS or surfactant. The lowered MLIs and cytokine levels and the increased VEGF expression and vascular density indicated that the surfactant and surfactant + MSCs (3 × 104 cells) treatment attenuated hyperoxia-induced lung injury. The surfactant + MSCs (3 × 105 cells) group exhibited a significantly lower MLI and significantly higher VEGF expression and vascular density than the surfactant + MSCs (3 × 104 cells) group did.Conclusions: Consecutive daily administration of intratracheal surfactant and MSCs can be an effective regimen for treating hyperoxia-induced lung injury in neonates.