DRD1 downregulation contributes to mechanical stretch-induced lung endothelial barrier dysfunction

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Pharmacology

Background:

• Ventilator-induced lung injury (VILI) is a significant clinical challenge.
• The role of dopamine and its receptors in VILI pathogenesis is not fully understood.

Purpose of the Study:

• To investigate dopamine receptor involvement in VILI.
• To explore the therapeutic potential of dopamine D1 receptor (DRD1) agonists in VILI.

Main Methods:

• Studied DRD1 knockout mice, mouse lung vascular endothelial cells, and human lung samples.
• Examined mechanical stretch-induced endothelial barrier dysfunction and lung injury.
• Investigated signaling pathways including HDAC6 and α-tubulin.

Main Results:

• DRD1 was downregulated in VILI models and patients.
• DRD1 agonists attenuated lung injury and endothelial barrier dysfunction.
• DRD1 signaling inhibited mechanical stretch-induced α-tubulin deacetylation via cAMP/EPAC-mediated inactivation of HDAC6.

Conclusions:

• DRD1 plays a novel protective role against VILI.
• DRD1 signaling regulates microtubule stability and protects lung endothelial barrier function.
• The DRD1/cAMP/EPAC/HDAC6 pathway offers potential therapeutic targets for VILI.