INTRODUCTION
Bronchopulmonary dysplasia (BPD) remains one of the most prevalent chronic lung diseases in premature infants, characterized by impaired alveolar development and long-term respiratory complications. Emerging research highlights the importance of inflammatory pathways, particularly NLRP3-mediated macrophage pyroptosis, in the pathogenesis of BPD. Pyroptosis, a pro-inflammatory form of cell death, contributes to excessive inflammation and tissue injury in the immature lung exposed to hyperoxia. In this context, betaine, a naturally occurring compound with well-established anti-inflammatory and antioxidant properties, has attracted scientific interest as a potential therapeutic candidate. By modulating molecular signaling pathways, including FOXO1 phosphorylation, betaine may offer protective effects against hyperoxia-induced lung injury and provide new insights into treatment strategies for BPD.
PATHOGENESIS OF BPD AND NLRP3-MEDIATED PYROPTOSIS
BPD pathogenesis is multifactorial, involving mechanical ventilation, oxygen toxicity, and inflammatory responses that disrupt normal lung development. Among these, macrophage-driven inflammation through NLRP3 inflammasome activation plays a central role. Hyperoxia significantly increases the expression of pyroptosis-associated proteins, leading to alveolar simplification and impaired vascular growth. Pyroptotic macrophages release inflammatory cytokines, which exacerbate pulmonary damage and hinder alveolarization. Therefore, targeting NLRP3-mediated macrophage pyroptosis has emerged as a promising therapeutic strategy to improve outcomes in preterm infants with BPD.
ROLE OF BETAINE IN ANTI-INFLAMMATORY MODULATION
Betaine acts as a methyl donor in metabolic processes and exerts strong anti-inflammatory and antioxidative functions. In the context of BPD, betaine reduces oxidative stress markers and inflammatory mediators while preserving lung tissue integrity. Experimental evidence demonstrates that daily subcutaneous administration of betaine in neonatal mice exposed to hyperoxia significantly reduces macrophage pyroptosis. By attenuating oxidative injury and inflammatory cytokine production, betaine supports both structural and functional lung protection, indicating its therapeutic potential.
FOXO1 PHOSPHORYLATION AND BETAINE INTERVENTION
The transcription factor FOXO1 is closely associated with cell survival, inflammation, and oxidative stress responses. Hyperoxia induces FOXO1 phosphorylation, which in turn promotes NLRP3 activation and pyroptosis in pulmonary macrophages. Betaine has been shown to inhibit the phosphorylation of FOXO1, thereby preventing NLRP3 activation and subsequent pyroptotic cell death. In vitro studies using RAW264.7 macrophages confirmed that betaine suppressed FOXO1 phosphorylation and pyroptosis under hyperoxic conditions, while treatment with okadaic acid, a phosphatase inhibitor, reversed these protective effects.
IMPACT ON LUNG DEVELOPMENT
Hyperoxia-induced injury impairs alveolarization, leading to fewer and larger alveoli typical of BPD. Betaine treatment has been found to restore alveolar structure, reduce inflammatory infiltration, and promote lung development in neonatal mice exposed to hyperoxia. By modulating molecular pathways and reducing macrophage pyroptosis, betaine indirectly supports lung growth and enhances overall pulmonary architecture. This suggests that betaine not only acts as an anti-inflammatory agent but also plays a crucial role in developmental lung protection.
FUTURE RESEARCH DIRECTIONS
The findings on betaine’s protective effects in hyperoxia-induced BPD provide a foundation for translational research. Future studies should focus on dose optimization, timing of administration, and long-term safety in neonatal populations. Investigating the interaction of betaine with other molecular pathways may also reveal synergistic therapeutic benefits. Clinical trials will be necessary to validate preclinical evidence and establish betaine as a viable adjunct therapy for preventing or treating BPD in preterm infants.
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