589 - Postnatal Administration of Mesenchymal Stromal Cell Extracellular Vesicles Attenuates Neonatal Pulmonary Hypertension in an Experimental Model of Pre-Eclampsia

Poster Number: 589
Publication Number: 589.1273

Background: Pre-eclampsia (PE) is responsible for nearly one-fourth of all preterm births and emerging evidence suggest that PE dysregulates angiogenesis, induces a pro-inflammatory milieu and contributes to bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). We previously demonstrated that antenatal administration of MSC-EVs preserves lung development in neonatal rats born to PE pregnancies. Here, we test the hypothesis that postnatal administration of MSC-EVs (Post-N MSC-EVs) will reduce lung inflammation and prevent experimental PE associated BPD and PH.

Objective: To determine whether intratracheal (IT) administration of Post-N MSC-EVs reduces lung inflammation, preserves lung alveolar and vascular development and prevents PH in pups born to pregnancies complicated by experimental PE.

Design/Methods: PE phenotype was induced in pregnant rats by administering L-NAME from embryonic day (E) 10-E20. Newborn pups were randomly assigned to receive IT Post-N MSC-EVs or placebo on postnatal (P) day 3. The mRNA expression of lung proinflammatory cytokines was determined by real-time (RT) PCR. The degree of alveolarization, lung angiogenesis, pulmonary hypertension (PH), and vascular remodeling was assessed on P7. Lung alveolarization was determined by measuring the mean linear intercept (MLI). Angiogenesis was assessed by quantifying lung vascular density. PH was determined by measuring the weight ratio of the right ventricle to left ventricle + septum (RV/LV+ S). Vascular remodeling was assessed by determining the percentage of muscularized vessels per high power field. Data are expressed as mean + SD and analyzed by ANOVA.

Results: Newborn pups born to pregnancies complicated by experimental PE exhibited an increase in the mRNA expression of lung inflammatory cytokines (CCL22, IL-7, IL-6) and inflammasome components (ASC, caspase-1), Fig. 1. This was accompanied by significantly increased MLI (Fig. 2A), decreased lung vascular density (Fig. 2B) and PH evidenced by increased RV/LV+S and vascular remodeling (Figs. 3A and 3B). In contrast, postnatal administration of IT Post-N MSC-EVs decreased the expression of lung inflammation markers, improved lung alveolar and vascular structures, attenuated PH and reduced vascular remodeling in newborn pups born to PE pregnancies (Figs. 1-3).

Conclusion(s): Postnatal MSC-EVs reduces lung inflammation, preserves lung alveolar and vascular development and prevents PH in newborn pups born to pregnancies complicated by experimental PE. These findings suggest that MSC-EVs may be a therapeutic strategy to prevent PE associated BPD and PH in preterm infants.