PHD Inhibition Accelerates Lung Growth in a Murine Model of Unilateral Pneumonectomy
*Victoria Ko, *Duy T Dao, *Lorenzo Anez-Bustillos, *Lumeng J Yu, *Bennet S Cho, *Amy Pan, *Mark Puder
Boston Children's Hospital, Boston, MA
Objective: Pulmonary hypoplasia (PH) remains a major cause of morbidity and mortality in newborns with congenital diaphragmatic hernia (CDH). PH is characterized by immature lung growth and development. VEGF has been demonstrated to promote pulmonary growth via angiogenesis. FG-4592, a prolyl hydroxylase inhibitor, increases endogenous VEGF by preventing the degradation of upstream regulatory factors, specifically HIF-2α, a well-known modulator of pulmonary development. We investigated the role of FG-4592 in accelerating lung growth.
Design: Mice were randomized into two groups, treatment with FG-4592 or control.
Participants: Fifty-nine eight-week old mice.
Interventions: Left pneumonectomy followed by twice daily intraperitoneal injections of FG-4592 or control.
Main Outcome Measures: On postoperative day four, lung tissue was harvested for lung volume measurements, morphometrics, RNA analysis and immunohistochemical staining.
Results: FG-4592 treatment demonstrated significant increase in lung volume. Morphometric data demonstrated significant increases in parenchymal volume, alveolar volume and total alveolar count. Quantitative PCR revealed significant increase in HIF-2α and VEGF-R2, the principle receptor of VEGF. Significant increases were seen in downstream targets of HIF-2α, surfactant proteins and CD31, an endothelial cell marker. This was correlated with a significant increase in the percentage of proliferating endothelial cells on immunohistochemistry.
Conclusions: FG-4592 administration accelerates pulmonary growth after unilateral pneumonectomy likely mediated through the upregulation of HIF-2α and VEGF. FG-4592 is currently in Phase III clinical trials for the treatment of anemia with minimal immediate side effects. Therefore, translation to use in the treatment of PH and diseases of pulmonary development such as CDH could proceed expeditiously.
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