Impaired taurine transport contributes to bronchopulmonary dysplasia: a systems biology analysis

Metabolic dysregulation is implicated in the development of bronchopulmonary dysplasia (BPD). Taurine is an essential amino acid and a critical molecule in oxidative phosphorylation that mechanistically modulates angiogenesis. Using a neonatal hyperoxia model supported by metabolomic and single-cell RNA-seq analyses, we showed that insufficient taurine contributes to alveolar simplification in BPD. To model BPD, Sprague-Dawley rat pups were exposed to >90% oxygen. Plasma and lungs were obtained for multiomics. Pups received tunicamycin or tauroursodeoxycholic acid to study mechanisms that modulate taurine metabolism. Taurine was administered as rescue therapy after identifying its depletion in the BPD lungs. Genes and proteins of oxidative phosphorylation were enriched in BPD lungs, whereas complex I (C-I) activity was paradoxically decreased. The reduction of taurine and taurine-dependent C-I core subunits, NADH Dehydrogenase Subunits 5 and 6 (ND5, ND6), in BPD lungs explains this C-I paradox. The accompanying increase of plasma taurine in BPD pups indicates a decreased taurine transport, which can be explained by the reduced glycosylation and increased degradation of the taurine transporter. The results of complementary treatments with tunicamycin and tauroursodeoxycholic acid, indicate that endoplasmic reticulum stress contributes to impaired taurine transport in BPD rat lungs. Taurine treatment increased the expression of ND5 and ND6, the percentage of proliferating general capillary endothelial cells, and alveolar complexity in BPD lungs. Our multiomic approach reveals that taurine enhances endothelial resilience by activating the unfolded protein response, and might clinically benefit premature lungs. This represents a distinct antioxidant mechanism not previously characterized in hyperoxic lung injury.