591 - Role of Inflammasome Inhibition in Experimental Model of Neonatal Hyperoxia Induced Bronchopulmonary Dysplasia and Cardiac Dysfunction in Adults Born Preterm

Poster Number: 591
Publication Number: 591.1131

Background: Adults born preterm are at increased risk of cardiopulmonary morbidities. However, little is known of the underlying mechanisms connecting neonatal hyperoxia (O2) exposure to these long-term cardiopulmonary consequences in adults born preterm. Inflammasome associated caspase-1, is a pro-inflammatory complex that mediates the activation of cytokines IL-1β, IL-18, and pore-forming protein Gasdermin-D. Here we test the hypothesis that caspase 1 inhibition prevents long-term cardiopulmonary consequences of preterm birth.

Objective: To determine if inhibition of the inflammasome cascade using caspase-1 inhibitor protects against neonatal O2-induced lung injury and cardiac dysfunction.

Design/Methods: Newborn mice (n=40) exposed to normoxia (RA) or hyperoxia (85% O2) from postnatal day (P) 1 to 14 were randomly assigned to receive daily intraperitoneal (IP) injections of caspase-1 inhibitor (VX-765, 50 ug/Kg) or DMSO as placebo (PL). The mouse pups were recovered in RA into adulthood until 3 months of age. The effect of caspase 1 inhibition on lung alveolarization, angiogenesis, pulmonary vascular remodeling was assessed by lung histology and immunostaining. Cardiac function was assessed by echocardiography. Data are expressed as mean ± SD. Statistical significance was evaluated by two-way ANOVA. A p < .05 was considered significant.

Results: Adult mice exposed to neonatal O2 had significant alveolar simplification as assessed by Radial Alveolar Count (RAC-Fig 1A) and Mean Linear Intercept (MLI-Fig 1B). They also had decreased lung angiogenesis assessed by vascular density count (Fig 2A) and increased vascular remodeling assessed by percent muscularized vessels (Fig 2B). Echocardiography also showed diastolic dysfunction in the adult rats exposed to neonatal hyperoxia (p < 0.05, RA vs HYP). Preventive treatment with VX-765 improved alveolar simplification, lung angiogenesis and vascular remodeling. Treatment with VX-765 did not improve diastolic dysfunction at 3 months of age.

Conclusion(s): Neonatal O2 exposure predisposes to cardiopulmonary morbidities in adults born preterm. Inhibition of caspase-1 improves lung alveolarization, angiogenesis and pulmonary vascular remodeling. However, caspase -1 inhibition did not improve cardiac dysfunction on echocardiography at 3 months age. Further mechanistic studies to determine the protective role of caspase-1 inhibition in the neonatal O2-induced lung injury would be necessary.