Caspase-1 inhibition mitigates neonatal hyperoxia-induced vascular and cardiopulmonary inflammation in neonatal rats.

There is a fundamental knowledge gap regarding the effects of neonatal hyperoxia exposure on the systemic vasculature and its repercussions on the cardiopulmonary system. Neonatal hyperoxia exposure induces a pro-inflammatory profile. However, the role of inflammation in the developing vascular tree and cardiopulmonary system is poorly understood. Caspase-1 mediates activation of inflammatory cytokines (IL-1β and IL-18) and gasdermin D (GSDMD), causing pyroptosis and inflammation. We hypothesized that caspase-1 is a critical contributor in neonatal hyperoxia-induced systemic vascular and cardiopulmonary inflammation and that caspase-1 inhibition attenuates hyperoxia-induced vascular stiffness, cardiopulmonary inflammation, and bronchopulmonary dysplasia (BPD) phenotype in a neonatal rat model. Newborn rats randomized to room air (RA) or hyperoxia (85% O2) from postnatal day (P) 1 to 14 received caspase-1 inhibitor, VX-765, or placebo. Hyperoxia-exposed pups had increased cardiovascular inflammation and fibrosis, aortic stiffness, pulmonary vascular rarefaction and remodeling, alveolar simplification, and right ventricular hypertrophy. Administration of a caspase-1 inhibitor decreased IL-1β and GSDMD gene and protein expression in the aorta and left ventricle. This was accompanied by reduced aortic stiffness and cardiac fibrosis, improved alveolar structure, pulmonary vascular density and vascular remodeling, and attenuation of right ventricular hypertrophy. Together, our findings suggest that inhibition of the caspase-1 pathway leads to decreased cardiopulmonary inflammation and remodeling. In conclusion, targeting caspase-1 signaling may be a therapeutic strategy to prevent the consequences of vascular and cardiopulmonary inflammation associated with preterm birth and oxygen therapy.