Bronchopulmonary dysplasia demonstrates dysregulated autotaxin/lysophosphatidic acid signaling in a neonatal mouse model.

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease affecting premature infants who require oxygen supplementation and ventilator therapy to support their underdeveloped lungs. Autotaxin (ATX), an enzyme that generates the bioactive phospholipid lysophosphatidic acid (LPA), which acts via G-protein coupled receptors, has been implicated in numerous pulmonary diseases. In this study, we explored the pathophysiological role of the ATX/LPA signaling pathway in BPD. Neonatal mice were exposed to normoxia or hyperoxia (85%) for 14 days from birth while being treated with vehicle, ATX inhibitor or LPA receptor 1 (LPA₁) inhibitor. In vitro studies utilized human lung fibroblast (HLF) cells exposed to room air, 85% oxygen, or LPA for varying time periods. Supernatants and cells were collected for assays and Western blotting. Animals exposed to hyperoxia showed elevated expression of ATX, ATX activity, and LPA₁. Inhibiting ATX or LPA₁ improved alveolarization, reduced inflammation, and mitigated extracellular matrix deposition and lysyl oxidase (LOX) expression. LPA₁ inhibition leading to reduced LOX expression was associated with a reduction in phosphorylation of AKT. Hyperoxia increases the expression of ATX and LPA₁ associated with increased LOX in the lungs. Targeting the ATX/LPA₁ pathway could be a potential therapeutic approach to BPD. Exposure to hyperoxia increases the expression and activity of autotaxin (ATX), as well as expression of LPA receptor 1 (LPA₁). Increased expression of ATX influences extra cellular matrix (ECM) remodeling. Inhibitors targeting the ATX/LPA pathway could offer a new therapeutic approach to bronchopulmonary dysplasia (BPD), potentially mitigating ECM deposition and improving lung development.