Prolyl Hydroxylase Inhibition Enhances Pulmonary Growth and Function - A Novel Treatment for Pulmonary Hypoplasia
Ko V, Dao DT, Yu LJ, Li XR, Anez-Bustillos L, Cho BS, Pan A, Puder M
Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA
Background: Pulmonary hypoplasia (PH) is a major cause of morbidity and mortality in newborns with congenital diaphragmatic hernia (CDH). PH is characterized by immature lung development. Vascular endothelial growth factor (VEGF) has previously been demonstrated to promote pulmonary development via angiogenesis. FG-4592, a prolyl hydroxylase inhibitor, increases endogenous VEGF by stabilizing upstream regulatory factors. We investigate the potential of FG-4592 treatment to accelerate pulmonary development in a model of compensatory lung growth (CLG).
Methods: Eight-week old male mice underwent left pneumonectomy followed by twice daily oral gavage of a vehicle control or FG-4592. On post-operative day four, exercise tolerance and pulmonary function tests (PFTs) were performed, followed by lung harvest for lung volume measurements, morphometrics and protein analysis.
Results: FG-4592 significantly improved exercise tolerance as evidenced by increased time spent exercising and distance traveled compared to controls. PFTs demonstrated a significant increase in total lung capacity, correlating with a significant increase in lung volume determined by the water displacement method. Morphometric analysis demonstrated significant increase in parenchymal volume, alveolar volume and total alveolar count. On immunoblot, VEGF expression was increased with simultaneous decrease of pigment-epithelium derived factor (PEDF), an anti-angiogenic protein.
Conclusion: FG-4592 treatment accelerates pulmonary development in a model of CLG. This is likely mediated through simultaneously increased VEGF and decreased PEDF. FG-4592 is currently in Phase III clinical trials for the treatment of anemia with minimal immediate side effects. Therefore, its use in the treatment of PH and diseases of pulmonary development such as CDH could proceed expeditiously.
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