Consecutive daily administration of intratracheal surfactant and human umbilical cord-derived mesenchymal stem cells attenuates hyperoxia-induced lung injury in neonatal rats

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. Our previous study found that mesenchymal stem cells (MSCs) attenuated hyperoxia-induced lung injury and the combination therapy of surfactant and human umbilical cord-derived MSCs (hUC-MSCs) did not have additive effects on hyperoxia-induced lung injury in neonatal rats. The aim is to evaluate the effects of 2 consecutive days of intratracheal administration of surfactant and hUC-MSCs on hyperoxia-induced lung injury. Methods Neonatal Sprague Dawley rats were reared in either room air (RA) or hyperoxia (85% O-2) from postnatal days 1 to 14. On postnatal day 4, the rats received intratracheal injections of either 20 mu L of normal saline (NS) or 20 mu L of surfactant. On postnatal day 5, the rats reared in RA received intratracheal NS, and the rats reared in O-2 received intratracheal NS or hUC-MSCs (3 x 10(4) or 3 x 10(5) cells). Six study groups were examined: RA + NS + NS, RA + surfactant + NS, O-2 + NS + NS, O-2 + surfactant + NS, O-2 + surfactant + hUC-MSCs (3 x 10(4) cells), and O-2 + surfactant + hUC-MSCs (3 x 10(5) cells). The lungs were excised for histological, western blot, and cytokine analyses. Results The rats reared in hyperoxia and treated with NS yielded significantly higher mean linear intercepts (MLIs) and interleukin (IL)-1 beta and IL-6 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 cytokines and the increased VEGF expression and vascular density indicated that the surfactant and surfactant + hUC-MSCs (3 x 10(4) cells) treatment attenuated hyperoxia-induced lung injury. The surfactant + hUC-MSCs (3 x 10(5) cells) group exhibited a significantly lower MLI and significantly higher VEGF expression and vascular density than the surfactant + hUC-MSCs (3 x 10(4) cells) group did. Conclusions Consecutive daily administration of intratracheal surfactant and hUC-MSCs can be an effective regimen for treating hyperoxia-induced lung injury in neonates.