Beta-3 Adrenoceptor (β3-AR) agonism is a promising strategy against bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is the most common lung disease affecting premature newborns, especially those who undergo respiratory distress syndrome and need clinical lifesaving measures, such as mechanical ventilation and oxygen supplementation. Preterm delivery can result in BPD, and among the various pathways implicated in the pathogenesis of BPD, the beta-3 adrenergic receptor (β3-AR) could represent a promising target for treatment due to its oxygen-dependent regulation, its ability to reduce oxidative stress, and its protective effect against neonatal intestinal hyperoxia-induced damage. To explore this hypothesis, we evaluated the effect of BRL37344, a commonly used β3-AR agonist, in a rat BPD-like model. Hyperoxia increased oxidative stress levels, resulting in decreased pulmonary volume, impaired alveolarization and vascularization, hyperplasia of type II alveolar cells, and fibrosis, ultimately leading to a reduced survival rate. The administration of BRL37344 at 3 mg/kg effectively counteracted these alterations, and the onset and the progression of the BPD-like disease. Our findings unveil a previously unrecognized role of the β3-AR in the onset/progression of BPD, paving the way for its pharmacological targeting as a new strategy for the prevention or treatment of this disease and other pulmonary disorders characterized by fibrosis.