Angiogenesis. 2020 Jul 14. doi: 10.1007/s10456-020-09735-9. [Epub ahead of print] https://pmlegacy.ncbi.nlm.nih.gov/pubmed/32666268
Roxadustat (FG-4592) accelerates pulmonary growth, development, and function in a compensatory lung growth model.
Ko VH1,2, Yu LJ1,2, Dao DT1,2, Li X1,2, Secor JD1,2, Anez-Bustillos L1,2, Cho BS1,2, Pan A1,2, Mitchell PD3, Kishikawa H1,2, Puder M4,5.
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Abstract
Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Current management of CDH is primarily supportive and mortality rates of the most severely affected children have remained unchanged in the last few decades. Previous work in our lab has demonstrated the importance of vascular endothelial growth factor (VEGF)-mediated angiogenesis in accelerating compensatory lung growth. In this study, we evaluated the potential for Roxadustat (FG-4592), a prolyl hydroxylase inhibitor known to increase endogenous VEGF, in accelerating compensatory lung growth. Treatment with Roxadustat increased lung volume, total lung capacity, alveolarization, and exercise tolerance compared to controls following left pneumonectomy. However, this effect was likely modulated not only by increased VEGF, but rather also by decreased pigment epithelium-derived factor (PEDF), an anti-angiogenic factor. Furthermore, this mechanism of action may be specific to Roxadustat. Vadadustat (AKB-6548), a structurally similar prolyl hydroxylase inhibitor, did not demonstrate accelerated compensatory lung growth or decreased PEDF expression following left pneumonectomy. Given that Roxadustat is already in Phase III clinical studies for the treatment of chronic kidney disease-associated anemia with minimal side effects, its use for the treatment of pulmonary hypoplasia could potentially proceed expeditiously.
KEYWORDS:
Compensatory lung growth; Pigment epithelium-derived factor; Pneumonectomy; Roxadustat; Vadadustat; Vascular endothelial growth factorPMID: 32666268 DOI: 10.1007/s10456-020-09735-9
