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 lethal Acute Respiratory Distress Syndrome (ARDS) with limited therapeutic options.
• Pediatric ARDS (PARDS) exhibits lower mortality than adult ARDS, suggesting age-related physiological differences.
• Rodent models show improved ALI measures in juvenile animals, hinting at distinct pathophysiological mechanisms.

Purpose of the Study:

• To investigate age-dependent differences in lung endothelial inflammatory signaling during ALI.
• To identify key molecular pathways involved in ALI pathophysiology in adult versus juvenile mice.
• To explore the role of Yes-associated protein (YAP) in ALI-induced inflammation.

Main Methods:

• Induction of pneumonia-induced ALI in adult and weanling mice.
• Analysis of endothelial inflammatory signaling, focusing on YAP.
• Transcriptomic analysis of lung endothelial cells to identify differential gene expression.
• Assessment of nuclear factor kappa-B (NF-κB) activation.
• Pharmacological blockade of YAP signaling.

Main Results:

• Pneumonia-induced ALI triggered YAP-dependent inflammatory signaling in adult mouse lung endothelium, absent in weanlings.
• Transcriptomic analysis revealed significantly increased NF-κB signaling in adult ALI lungs compared to weanlings.
• Blockade of YAP signaling ameliorated inflammatory responses, hypoxemia, and NF-κB translocation in adult mice with ALI.
• A distinct signaling cascade in adult lung endothelium during ALI was identified.

Conclusions:

• An age-dependent YAP-NF-κB signaling cascade in the lung endothelium contributes to ALI pathophysiology in adult mice.
• This pathway is not present in weanling mice, explaining potential differences in ALI/ARDS outcomes.
• Targeting age-specific pathways like YAP signaling may lead to novel therapeutic strategies for ARDS in different age groups.