Unphysiological lung strain promotes ventilation-induced lung injury via activation of the PECAM-1/Src/STAT3 signaling pathway.

Summary

In a rat VILI model, unphysiological lung strain activated PECAM-1 and downstream Src/STAT3 signaling, triggering inflammatory pyroptosis. Pharmacologic inhibition of PECAM-1 or Src/STAT3 mitigated lung injury and inflammatory responses, with in vitro validation under mechanical stretch.

Key Findings

• UPLS activated PECAM-1 and downstream Src/STAT3 signaling, increasing inflammation and pyroptosis in a rat VILI model.
• Inhibiting PECAM-1 or Src/STAT3 reduced lung injury, inflammatory responses, and pyroptosis.
• PECAM-1 inhibition decreased activation of the Src/STAT3 pathway; mechanism corroborated in HUVECs under cyclic stretch.

Clinical Implications

Reinforces minimizing unphysiological strain (e.g., low driving pressure, careful PEEP titration) to prevent VILI; suggests PECAM-1/Src/STAT3 as candidate targets for adjunctive therapies, pending translational validation.

Limitations

• Preclinical rat model limits direct clinical generalizability
• Lack of genetic knockdown/knockout approaches to complement pharmacologic inhibition

Future Directions

Test PECAM-1/Src/STAT3 modulation in larger animal models and explore biomarkers of pathway activation in ARDS patients under varying ventilator settings.