Aberrant Autotaxin/Lysophosphatidic Acid Signaling in the Pathogenesis of Bronchopulmonary Dysplasia

Abstract Bronchopulmonary dysplasia (BPD), a chronic lung disease affecting the developing lung of a premature infant, affects nearly 10,000 infants in the US each year. Oxygen supplementation/mechanical ventilation, while a necessary therapy to treat critically ill infants, leads to oxygen toxicity and volutrauma, and is one of the most prevalent postnatal risk factors of BPD. BPD is characterized by an arrest in alveolarization, resulting in fewer alveoli in the lung, creating an ineffective area for gas exchange to occur. Children who had BPD as infants are more susceptible to chronic respiratory impairments such as wheezing, coughing, and asthma. Current therapy options aim to reduce the incidence of BPD, as well as promote lung growth and development. Lysophosphatidic acid (LPA), the simplest bioactive phospholipid, mediates diverse biological processes such as cell proliferation, cell survival, and chemotaxis following its binding of specific G protein-coupled receptors, LPA1-6. LPA is derived from membrane phospholipids, primarily through the actions of the enzyme, autotaxin (ATX). The ATX-LPA signaling axis has been implicated in numerous lung pathologies, including idiopathic pulmonary fibrosis, asthma, and lung cancer. Recently, the role of ATX-LPA in pathogenesis is beginning to be explored. Our studies show that expression and activity of ATX is significantly modulated in a hyperoxia- induced lung injury model of BPD in neonatal mouse pups. Inhibiting ATX activity in vivo ameliorated hyperoxia-mediated changes in the lung’s architecture, lung injury, and function. Further, we identified LPA1 to be significantly expressed following oxygen exposure in vivo and in vitro, and that LPA1 antagonism protected mice from hyperoxia-induced lung injury. Our data suggest that targeting the ATX/LPA/LPA1 signaling axis could be beneficial in the pathogenesis of neonatal BPD.