Unique Heterogeneous Topological Pattern of the Metabolic Landscape in Rabbit Fetal Lungs following Tracheal Occlusion

Abstract

Introduction: Fetal tracheal occlusion (TO) is currently an experimental approach to drive accelerated lung growth. It is stimulated by mechanotransduction that results in increased cellular proliferation and growth. However, it is currently unknown how TO affects the metabolic landscape of fetal lungs. Materials and Methods: TO or sham was performed on fetal rabbits at 26 days followed by lung harvest on day 30. Mass spectrometry was performed to evaluate global metabolic changes. Fluorescence lifetime intensity microscopy (FLIM) was performed to estimate local free/bound NADH relative ratio as an indicator of aerobic glycolysis versus oxidative phosphorylation (glycolysis/OXPHOS). Results: TO results in a metabolic shift from tricarboxylic acid cycle towards glycolysis. FLIM reveals uniform structures in control lungs characterized by similar ratios of free/bound NADH indicating a homogenous topological pattern. Similar uniform structures are observed in shams with some variability in the glycolysis/OXPHOS ratio. In contrast, lungs following TO demonstrate different types of unique distinct topological zones: one with enlarged alveoli and a shift towards glycolysis; the other maintains balance between glycolysis/OXPHOS similar to control lungs. Conclusion: We demonstrate for the first time a unique variable topological pattern of metabolism in fetal lungs following TO with a wide variation of metabolism between zones.