In the realm of neonatal medicine, bronchopulmonary dysplasia (BPD) continues to pose a significant clinical challenge, particularly in premature infants exposed to supplemental oxygen. This chronic lung disease, characterized by impaired alveolar development and persistent inflammation, often leads to lifelong respiratory complications. Recent advances suggest a new therapeutic avenue that harnesses the potential of glucagon-like peptide-1 (GLP-1), a hormone classically known for its role in glucose metabolism. A groundbreaking study now reveals how GLP-1 analogs might revolutionize treatment paradigms by mitigating hyperoxia-induced lung injury through intricate molecular pathways involving the ACE-2/Ang(1-7)/Mas receptor axis.
BPD’s pathogenesis is complex, underpinned by oxidative stress from oxygen therapy—an essential yet double-edged sword in neonatal care. Excessive oxygen levels, while lifesaving, trigger inflammatory cascades and disrupt normal lung development, ultimately leading to the hallmark features of BPD: arrested alveolarization and vascular dysmorphogenesis. Conventional management strategies remain largely supportive, emphasizing the pressing need for targeted therapies that address the underlying molecular drivers. Against this backdrop, the emerging role of GLP-1 analogs opens a compelling frontier for intervention.
The recent investigation focused specifically on Liraglutide, a GLP-1 receptor agonist with established clinical use in diabetes management, probing its efficacy in a hyperoxia-induced neonatal mouse model of BPD. By exposing neonatal mice to sustained high oxygen levels mimicking clinical hyperoxic conditions, researchers effectively induced the phenotype of BPD. The administration of Liraglutide resulted in markedly improved pulmonary outcomes evidenced by enhanced alveolar architecture and reduced inflammatory markers, highlighting its potential as a lung-protective agent beyond glycemic control.
Intriguingly, the protective effects of Liraglutide correlated strongly with modulation of the ACE-2/Ang(1-7)/Mas receptor pathway, which has gained attention as a critical regulator of pulmonary homeostasis. ACE-2 (angiotensin-converting enzyme 2) catalyzes the conversion of Angiotensin II, a vasoconstrictive and pro-inflammatory peptide, into Ang(1-7), which exerts vasodilatory, anti-inflammatory, and anti-fibrotic actions via the Mas receptor. This axis thus represents a natural counterbalance to lung injury and fibrosis. The study’s molecular assays demonstrated that Liraglutide reinstates this protective signaling axis, countering hyperoxia-induced downregulation.
Beyond these mechanistic insights, the data illuminated how GLP-1 analogs modulate inflammatory cell infiltration and oxidative stress markers in the lung microenvironment. Hyperoxia typically amplifies neutrophil recruitment and generates reactive oxygen species (ROS), fostering injury. However, Liraglutide treatment diminished these pathological hallmarks, aligning with a shift toward a reparative, anti-inflammatory milieu. This suggests the drug not only halts degenerative changes but actively promotes lung regeneration and repair, a finding with profound therapeutic implications.
The translational significance of this research is considerable. Neonates with BPD currently have limited pharmacological options, and the systemic side effects of existing therapies often complicate treatment. Liraglutide, already approved with a well-characterized safety profile, could be rapidly repositioned for neonatal applications pending rigorous clinical trials. Moreover, its dual role in metabolic and pulmonary modulation heralds a new class of multifunctional therapeutics tailored to vulnerable preterm populations.
Scientific exploration into the ACE-2/Ang(1-7)/Mas receptor axis further frames this study within the larger context of pulmonary vascular biology. Given that this signaling pathway intersects with pathways implicated in COVID-19 and other pulmonary pathologies, the findings may extend benefits to a broad spectrum of respiratory disorders characterized by oxidative stress and inflammation. The crosstalk between GLP-1 signaling and renin-angiotensin system components represents a fertile ground for future drug development.
In addition to histological and biochemical analyses, the research employed advanced imaging techniques to quantify alveolar simplification and vascular rarefaction. Such comprehensive phenotyping fortifies the conclusion that Liraglutide can restore lung architecture disrupted by hyperoxic exposure. This prescient use of quantitative lung morphometry underscores the importance of integrating cutting-edge methodologies in preclinical studies to enhance the robustness and reproducibility of findings.
Another compelling dimension unveiled is the potential neuroprotective role of GLP-1 analogs. Although the current study centers on lung pathology, emerging evidence links systemic inflammation and oxidative stress in BPD to neurodevelopmental impairment. By attenuating inflammatory cascades and oxidative insults, Liraglutide may confer ancillary neuroprotection, a hypothesis warranting further investigation. Such dual organ protection would elevate the clinical value of GLP-1 receptor agonists in neonatal intensive care.
The study also lays groundwork for disaggregating the precise molecular mechanisms through which Liraglutide upregulates ACE-2 expression in pulmonary tissues. Whether this occurs via transcriptional activation, mRNA stabilization, or epigenetic modifications remains an open question. Deciphering these regulatory layers could not only optimize therapeutic dosing but also reveal novel drug targets within the lung’s molecular circuitry.
Furthermore, the research highlights the importance of timing in therapeutic intervention. Administration of Liraglutide during critical windows of lung development was pivotal to observed benefits. This temporal specificity aligns with the concept of developmental plasticity, emphasizing early modulation of pathogenic pathways to redirect disease trajectories. Future clinical translations must rigorously define such windows to maximize efficacy in preterm infants.
Importantly, safety considerations in neonatal populations remain paramount. Although Liraglutide’s profile is reassuring in adults, neonatal pharmacodynamics and pharmacokinetics differ substantially, necessitating detailed toxicological and dosing studies. The current preclinical evidence serves as a pivotal step toward such evaluations but underscores the need for cautious and methodical clinical translation.
In a broader biomedical context, this study exemplifies the power of repurposing metabolic drugs to address complex, multifactorial diseases. The convergent evolution of metabolic and inflammatory pathways in diverse organ systems suggests that hormones like GLP-1 may serve as master regulators of homeostasis. Harnessing this potential could redefine therapeutic strategies across a range of chronic conditions beyond pulmonary medicine.
The implications of GLP-1-based therapies also extend to personalized medicine. Genetic variability in the ACE-2/Ang(1-7)/Mas receptor axis components may influence susceptibility to BPD and treatment response. Integrating genomic profiling with pharmacotherapy could tailor interventions for maximal benefit, ushering in a new era of precision neonatology.
This pioneering research ultimately opens a promising chapter in the battle against bronchopulmonary dysplasia, offering hope for improved outcomes in a vulnerable patient population. By illuminating the mechanisms that underlie GLP-1 analogs’ protective effects, it charts a course for innovative therapies grounded in molecular pathophysiology. As the neonatal intensive care community grapples with the persistent burden of BPD, such advances bring renewed optimism for transforming lives from the earliest moments.
Subject of Research: Bronchopulmonary dysplasia (BPD) and the therapeutic effects of GLP-1 analog Liraglutide via ACE-2/Ang(1-7)/Mas receptor pathway in a hyperoxia-induced neonatal mouse model.
Article Title: Bronchopulmonary dysplasia induced by hyperoxia attenuated by a GLP-1 analog, Liraglutide, by regulating the ACE-2/Ang(1-7)/Mas receptor pathway.
Article References:
Huang, B., Luo, H., Chen, R.Y. et al. Bronchopulmonary dysplasia induced by hyperoxia attenuated by a GLP-1 analog, Liraglutide, by regulating the ACE-2/Ang(1-7)/Mas receptor pathway. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04293-6
Image Credits: AI Generated
