245 - Inhaled Sildenafil and Preterm Umbilical Cord Derived Mesenchymal Stem Cell Exosomes for Prevention of Murine Bronchopulmonary Dysplasia

Publication Number: 4241.245

Caitlin E. Jackson, University of California, Irvine, School of Medicine, Orange, CA, United States; Fayez Bany-Mohammed, University of California, Irvine, Irvine, CA, United States; Cherry Uy, University of California, Irvine, School of Medicine, Orange, CA, United States; Muhammad Aslam, UC Irvine, Orange, CA, United States

Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants characterized by impaired alveolarization, disrupted vascular development, and pulmonary hypertension. Studies have shown that intravenous administration of mesenchymal stem cells (MSCs) and their exosomes (MSC-exo) can prevent BPD in murine models, likely via paracrine and immunomodulatory effects. Pulmonary hypertension in BPD responds to Sildenafil, but systemic delivery may limit local efficacy and increase side effects. Direct pulmonary delivery can achieve higher local concentrations, reduce systemic exposure, and enhance therapeutic efficiency. We developed a novel inhalation system to deliver Sildenafil and MSC-exo directly to the lungs.

Objective: We hypothesized that inhalation of Sildenafil combined with preterm MSC-exo is feasible and therapeutically beneficial in preventing BPD. Our objectives were to evaluate lung injury and pulmonary hypertension in hyperoxia-exposed murine models treated with inhaled Sildenafil and MSC-exo.

Design/Methods: MSCs were isolated from preterm umbilical cords (24-28 weeks' gestational age) and exosomes generated. FVB mice were exposed to hyperoxia (90% O₂) within 24 hours of birth; controls remained in normoxia (21% O₂). One group received daily inhalation of MSC-exo (0.1 μg/g body weight) with Sildenafil (0.5 mg/kg) from postnatal days 7 to 21. Comparison groups received MSC-exo alone, Sildenafil alone, or human skin epithelium cell-derived exosomes (SEC-exo). Animals remained in hyperoxia until day 14, then in normoxia until day 28. Lung function was assessed via pulmonary function testing, and echocardiography evaluated right ventricular hypertrophy and pulmonary artery acceleration time as measures of pulmonary hypertension.

Results: Combined inhalation of Sildenafil and preterm MSC-exo protected against hyperoxia-induced lung injury, improving inspiratory capacity and lung compliance compared with monotherapy or SEC-exo controls (Fig. 1). The combination also prevented pulmonary hypertension, demonstrated by reduced right ventricular hypertrophy and improved pulmonary artery acceleration time (Fig. 2). All differences were statistically significant, indicating a synergistic effect of MSC-exo and Sildenafil when delivered directly to the lungs.

Conclusion(s): Direct pulmonary delivery of Sildenafil combined with MSC-exo is feasible and effective in mitigating hyperoxia-induced BPD in murine models. Ongoing studies are evaluating extended treatment duration, optimal dosing, and mechanistic pathways underlying the observed therapeutic effects.

Figure 1
Lung Function Assessment in Treated Animals

Figure 2
Pulmonary Hypertension Assessment in Treated Animals