579 - Inflammasome Inhibition as a Therapeutic Strategy in Experimental Bronchopulmonary Dysplasia and Cardiac Fibrosis

Poster Number: 579
Publication Number: 579.1253

Background: Inflammation is a key contributor to aberrant lung development and remodeling in preterm infants with bronchopulmonary dysplasia (BPD). Inflammasomes are intracellular multiprotein complexes that when triggered by oxidative stress oligomerizes and promotes the activation of Caspase-1, a key factor in the pathogenesis of BPD. Previously, we demonstrated that inflammasome inhibition protected against cardiovascular inflammation in neonatal rodents exposed to hyperoxia (O2). Here we test the hypothesis that Caspase 1 inhibition is a therapeutic strategy to prevent BPD, and cardiac fibrosis.

Objective: To determine whether Caspase-1 inhibition attenuates hyperoxia-induced lung injury and cardiac fibrosis in a neonatal murine model.

Design/Methods: Newborn rat pups (n=10-20/group) randomly assigned to normoxia (RA) or hyperoxia (85% O₂) from postnatal day (P)1 to 14, received daily intraperitoneal injections of Caspase-1 inhibitor VX-765 (50mg/kg), or placebo (PL). Alveolar development was assessed by Mean Linear Intercept (MLI) and Radial Alveolar Count (RAC). Lung angiogenesis was assessed by quantifying vascular density. Vascular remodeling was assessed by determining the percent of muscularized vessels per high power field (HPF). Fulton index was analyzed to assess right ventricular hypertrophy (RVH) and Masson’s Trichrome staining was used to assess cardiac fibrosis. Data are expressed as mean ± SEM and analyzed by two-way ANOVA.

Results: There was no significant difference between RA groups. Hyperoxia exposed pups had marked vascular rarefaction, alveolar simplification, remodeling, RVH and cardiac fibrosis. This was evidenced by decreased lung vascular density, increased MLI, decreased RAC and increased muscularized vessels, increased RVH and cardiac fibrosis (p < 0.05, RA vs hyperoxia). Administration of Caspase 1 inhibitor, VX-765 significantly improved alveolar structure, vascular density, vascular remodeling, right ventricular hypertrophy, and cardiac fibrosis. (Figure 1 and 2).

Conclusion(s): Caspase-1 inhibition improves alveolarization, angiogenesis, pulmonary vascular remodeling, RVH and decreases cardiac fibrosis in neonatal rats exposed to hyperoxia. Further mechanistic studies elucidating the mechanistic role of inflammasome signaling in lung of rodents exposed to neonatal hyperoxia would be necessary.