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Efficacy of Leukadherin-1 in the Prevention of Hyperoxia-Induced Lung Injury in Neonatal Rats
Jawahar Jagarapu1, Jelte Kelchtermans1, Min Rong1
11 Department of Pediatrics, Division of Neonatology, Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, Florida; and.
Insights
Leukadherin-1 (LA1) reduces lung inflammation in a neonatal rat model of bronchopulmonary dysplasia (BPD). This novel treatment improves lung development and prevents pulmonary hypertension, offering a potential new strategy for preterm infants.
Area of Science:
- Neonatal research
- Pulmonary medicine
- Inflammation and immunology
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants, driven by lung inflammation.
- Current BPD management lacks effective and safe anti-inflammatory therapies.
- Leukadherin-1 (LA1) is a novel integrin agonist that modulates leukocyte adhesion and migration.
Purpose of the Study:
- To investigate the efficacy of Leukadherin-1 (LA1) in preventing hyperoxia-induced neonatal lung injury, an experimental model of BPD.
- To test the hypothesis that LA1 administration is beneficial in mitigating BPD-like lung pathology.
Main Methods:
- Newborn rats were exposed to hyperoxia (85% O2) or normoxia (21% O2) for 14 days.
- Animals received twice-daily intraperitoneal injections of LA1 or a placebo.
- Lung injury, leukocyte infiltration, alveolarization, angiogenesis, and pulmonary hypertension were assessed.
Main Results:
- Hyperoxia with placebo increased neutrophil and macrophage influx, decreased alveolarization and angiogenesis, and worsened pulmonary vascular remodeling and hypertension.
- LA1 treatment significantly reduced macrophage infiltration in hyperoxic lungs.
- LA1 administration improved alveolarization and angiogenesis while decreasing pulmonary vascular remodeling and hypertension.
Conclusions:
- Leukocyte recruitment is a critical factor in hyperoxia-induced neonatal lung injury, a model for BPD.
- Targeting leukocyte trafficking with LA1, an integrin agonist, effectively reduces lung inflammation and protects lung structures.
- LA1 represents a promising novel therapeutic strategy for preventing and treating BPD in preterm infants.
Abstract:
Lung inflammation plays a key role in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants. The challenge in BPD management is the lack of effective and safe antiinflammatory agents. Leukadherin-1 (LA1) is a novel agonist of the leukocyte surface integrin CD11b/CD18 that enhances leukocyte adhesion to ligands and vascular endothelium and thus reduces leukocyte transendothelial migration and influx to the injury sites. Its functional significance in preventing hyperoxia-induced neonatal lung injury is unknown. We tested the hypothesis that administration of LA1 is beneficial in preventing hyperoxia-induced neonatal lung injury, an experimental model of BPD. Newborn rats were exposed to normoxia (21% O2) or hyperoxia (85% O2) and received twice-daily intraperitoneal injection of LA1 or placebo for 14 days. Hyperoxia exposure in the presence of the placebo resulted in a drastic increase in the influx of neutrophils and macrophages into the alveolar airspaces. This increased leukocyte influx was accompanied by decreased alveolarization and angiogenesis and increased pulmonary vascular remodeling and pulmonary hypertension (PH), the pathological hallmarks of BPD. However, administration of LA1 decreased macrophage infiltration in the lungs during hyperoxia. Furthermore, treatment with LA1 improved alveolarization and angiogenesis and decreased pulmonary vascular remodeling and PH. These data indicate that leukocyte recruitment plays an important role in the experimental model of BPD induced by hyperoxia. Targeting leukocyte trafficking using LA1, an integrin agonist, is beneficial in preventing lung inflammation and protecting alveolar and vascular structures during hyperoxia. Thus, targeting integrin-mediated leukocyte recruitment and inflammation may provide a novel strategy in preventing and treating BPD in preterm infants.
