Betaine improves hyperoxic lung injury through downregulating pulmonary macrophage pyroptosis in newborn mice.

Background: Bronchopulmonary dysplasia (BPD) is a common chronic respiratory disease in preterm infants. NLRP3-mediated macrophage pyroptosis plays a crucial role in the pathogenesis of BPD. Recent evidence suggests that betaine has anti-inflammatory and antioxidant functions. This study aimed to investigate the effect of betaine on pulmonary macrophage pyroptosis in BPD.

Methods: Newborn mice were exposed to either hyperoxia (90%) or room air shortly after birth and treated subcutaneously with betaine daily for 14 days. Lung development, the expression of macrophage pyrolysis-associated proteins and the phospho-forkhead box O1 (p-FOXO1) were evaluated. In vitro, the effect of betaine on the expression of p-FOXO1 was assessed in RAW264.7 macrophages exposed to either 90% oxygen or 21% oxygen, with okadaic acid (OA) as phosphatase inhibitor.

Results: Hyperoxia induced macrophage pyroptosis and impaired lung development in newborn mice. Betaine inhibited p-FOXO1 expression and NLRP3-mediated pyroptosis in pulmonary and promoted lung development in the hyperoxia-exposed mice. In vitro, betaine suppressed FOXO1 phosphorylation and NLRP3-mediated pyroptosis under 90% oxygen in RAW264.7 cells, and OA administration reversed these effects.

Conclusion: Betaine may reduce the expression of inflammatory cytokines, downregulate macrophage pyroptosis by inhibiting the phosphorylation of FOXO1, and improve lung development in BPD.

Impact: Our previous research showed that plasma betaine levels at 36 weeks postmenstrual age (PMA) were significantly lower in preterm infants with BPD compared to those without BPD. Betaine has anti-inflammatory and antioxidant functions. However, its role in pulmonary macrophage pyroptosis in BPD remains unknown. The study shows that betaine may downregulate macrophage pyroptosis by inhibiting FOXO1 phosphorylation, alleviate lung inflammation, and improve lung development in BPD.