Ceramides as Therapeutic Targets in Bronchopulmonary Dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disorder associated with extremely premature birth, resulting from arrested development of the microvasculature and consequently disrupted alveologenesis. Premature infants are dependent on respiratory support, including oxygen supplementation and mechanical ventilation (MV), that are considered the main modifiable contributors to BPD. The mechanistic link between the injurious stimulus (e.g., hyperoxia) and disrupted lung development has been less clear. Recent works suggest the up regulation of ceramides in the injured lung as a potentially key factor. Ceramides regulate tissue growth pathways, by increasing autophagy and apoptosis. Ceramides are increased in tracheal aspirates of preterm infants receiving MV. Moreover, attenuation of ceramide synthesis by Sphingomyelin Phosphodiesterase 1 (SMPD1) inhibition prevented MV induced cell death in experimental animals. Whether ceramides may play a role in hyperoxia-induced lung injury remains less studied. To examine this issue, I employed an experimental rat model of BPD caused by exposure to hyperoxia for 14 days (85% O₂ postnatal days [PND] 1-7 and 60% O₂ PND 7-14) followed by intermittent hypoxia from PND 14-21 (termed the HIH BPD-like lung injury model). Lung injury in this model was characterized by hypoplastic pulmonary vasculature, pulmonary hypertension, and "emphysematous" lung structure due to inhibited alveologenesis. My findings demonstrated that exposure to severe hyperoxia (PND 1-7) lead to a rapid increase in the lung of pro-apoptotic ceramides, commencing on PND 1 and persisting to PND 7. Lung autophagy markers were up-regulated concurrent with increased ceramides, which was followed by increased apoptosis on PND 7, predominantly in distal lung epithelial cells. Treatment of HIH-exposed rat pups with daily S.C Desipramine 10 mg/kg/d (an SMPD1 inhibitor) prevented up-regulated lung ceramide content, autophagy, and apoptosis. Desipramine also prevented HIH-induced lung inflammation, vascular hypoplasia and pulmonary hypertension and partially improved markers of distal alveolar development. I also examined contents of four key ceramide pathway proteins in human autopsy-derived lung sections from infants with and without BPD, which revealed a significant increase in ceramide pathway proteins in BPD lungs when compared to controls. Coupled with earlier work, my findings support a key role for up-regulated ceramides in both human and experimental chronic neonatal lung injury. Inhibition of injurious ceramide production with Desipramine represents a promising strategy for the prevention of BPD.