Premature infants are born with developing lungs burdened by
surfactant deficiency and a dearth of
antioxidant defense systems. Survival rate of such infants has significantly improved due to advances in care involving
mechanical ventilation and
oxygen supplementation. However, a significant subset of such survivors develops the chronic
lung disease,
Bronchopulmonary dysplasia (BPD), characterized by enlarged, simplified alveoli and deformed airways. Among a host of factors contributing to the pathogenesis is oxidative damage induced by exposure of the developing lungs to
hyperoxia. Recent data indicate that
hyperoxia induces aberrant
sphingolipid signaling, leading to
mitochondrial dysfunction and abnormal
reactive oxygen species (ROS) formation (ROS). The role of
sphingolipids such as
ceramides and
sphingosine 1-phosphate (S1P), in the development of BPD emerged in the last decade. Both
ceramide and S1P are elevated in tracheal aspirates of premature infants of <32 weeks gestational age developing BPD. This was faithfully reflected in the murine models of
hyperoxia and BPD, where there is an increased expression of
sphingolipid metabolites both in lung tissue and bronchoalveolar lavage. Treatment of neonatal pups with a
sphingosine kinase1 specific inhibitor,
PF543, resulted in protection against BPD as neonates, accompanied by improved lung function and reduced
airway remodeling as adults. This was accompanied by reduced mitochondrial ROS formation. S1P receptor1 induced by
hyperoxia also aggravates BPD, revealing another potential druggable target in this pathway for BPD. In this review we aim to provide a detailed description on the role played by
sphingolipid signaling in
hyperoxia induced
lung injury and BPD.