Age-dependent Inflammatory Signaling in the Pulmonary Endothelium

Acute Lung Injury (ALI) causes the highly lethal Acute Respiratory Distress Syndrome (ARDS) in children and adults, for which therapy is lacking. Children with Pediatric ARDS (PARDS) have a mortality rate that is about half of adults with ARDS. Improved ALI measures can be reproduced in rodent models with juvenile animals, suggesting that physiologic differences may underlie these different outcomes. Here, we show that pneumonia-induced ALI caused inflammatory signaling in the endothelium of adult mice which depended on Yes-associated protein (YAP). This signaling was not present in 21-day-old weanling mice. Transcriptomic analysis of lung endothelial responses revealed nuclear factor kappa-B (NF-kB) as significantly increased with ALI in adult versus weanling mice. Blockade of YAP signaling protected against ALI and NF-kB nuclear translocation in adult mice. Our results demonstrate an important signaling cascade in the lung endothelium of adult mice that is not present in weanlings. We suggest other pathways may also exhibit age-dependent inflammatory signaling, which would have important implications for therapeutics in the adult and pediatric age groups. Overall design: Bulk RNA-seq of freshly isolated endothelial cells from weanling (P21) and adult (10 week old) C57BL/6J mice 24h after induction of pneumonia by intranasal instillation of Pseudomonas aeruginosa and saline (controls).