Yes-associated protein induces age-dependent inflammatory signaling in the pulmonary endothelium

Area of Science:

• Pulmonary Medicine
• Cellular Signaling
• Inflammation Research

Background:

• Acute lung injury (ALI) leads to acute respiratory distress syndrome (ARDS), a condition with limited therapeutic options and higher mortality in adults compared to children.
• Physiological differences between adult and juvenile animals may explain the disparity in ALI/ARDS outcomes, as suggested by rodent model studies.

Purpose of the Study:

• To investigate age-dependent differences in inflammatory signaling pathways within the lung endothelium during pneumonia-induced ALI.
• To determine the role of Yes-associated protein (YAP) signaling in ALI pathogenesis in adult versus juvenile mice.

Main Methods:

• Pneumonia-induced ALI model in adult and 21-day-old weanling mice.
• Analysis of endothelial inflammatory signaling, including YAP and nuclear factor-kappa B (NF-κB) activation.
• Transcriptomic analysis of lung endothelial cells.
• Pharmacological blockade of YAP signaling in adult mice.

Main Results:

• Pneumonia-induced ALI triggered inflammatory signaling in adult mouse lung endothelium, dependent on YAP, but this was absent in weanling mice.
• Transcriptomic analysis revealed significantly increased NF-κB activation in adult ALI lungs compared to weanlings.
• Blockade of YAP signaling in adult mice attenuated inflammation, hypoxemia, and NF-κB translocation during *Pseudomonas aeruginosa* pneumonia.

Conclusions:

• A YAP-dependent signaling cascade in adult lung endothelium contributes to ALI pathogenesis and is absent in weanling mice.
• These age-dependent signaling differences may partly explain better outcomes in pediatric ARDS compared to adult ARDS.
• Targeting age-specific pathways presents a potential therapeutic strategy for ARDS in different age groups.