Oxygen-induced metabolic changes and transdifferentiation in immature fetal rat lung lipofibroblasts

Abstract

Preterm infants lack adequate surfactant production and often require oxygen support for adequate oxygenation. Prolonged oxygen treatment leads to the development of bronchopulmonary dysplasia (BPD), a disease process characterized by the blunting of alveolarization and proliferation of myofibroblasts. In the present study, we investigated metabolic adaptive changes in cultured fibroblasts isolated from immature (d18) and near-term (d21), fetal rat lungs in response to normoxic (21%) and hyperoxic (95%) exposures. We used the [1,2- 13C 2] d-glucose tracer and gas chromatography/mass spectrometry to characterize glucose carbon redistribution between the nucleic acid ribose, lactate, and palmitate synthetic pathways, and reverse transcriptase-polymerase chain reaction to assess adipose differentiation related protein (ADRP) mRNA expression in response to hyperoxic exposure. Exposure to hyperoxia at each passage caused decrease (*, p<0.05 vs. 21% O 2) in ADRP mRNA expression in the d18 fibroblasts. This passage-dependent transdifferentiation is accompanied by a moderate (9–20%) increase in the synthesis of nucleic acid ribose from glucose through the non-oxidative steps of the pentose cycle. In contrast, d18 fibroblasts showed over an 85% decrease in the de novo synthesis of palmitate from glucose, while d21 fibroblasts showed a less pronounced 32–38% decrease in de novo lipid synthesis in hyperoxia-exposed cultures. It can be concluded from these studies that: (1) there is a maturation dependent sensitivity to hyperoxia; (2) transdifferentiation of flbroblast as demonstrated by changes in ADRP expression is accompanied by metabolic enzymes changes affecting ribose acid synthesis from glucose, and (3) hyperoxia specifically inhibits lipogenesis from glucose. Hyperoxia-induced metabolic changes thus play a key role in the transdifferentiation of lung fibroblasts to myofibroblasts and the pathogenesis of BPD.