Platelet-mediated activation of perivascular mast cells triggers progression of sepsis to septic shock in mice.

Summary

In murine sepsis, platelets adhere to vascular walls and activate perivascular mast cells via PAF, driving hypotension, vascular leak, and microvascular dysfunction that culminate in septic shock. Blocking platelet/MC activation or inhibiting mast cell chymase prevents shock progression and reduces mortality, revealing a tractable pathway.

Key Findings

• Sepsis activates platelets to adhere to vascular walls and release PAF, stimulating perivascular mast cells.
• Mast cell activation correlates with shock and mechanistically drives hypotension, vascular leakage, and microvascular dysfunction.
• Inhibiting platelet or mast cell activation, or blocking mast cell chymase, prevents progression to shock and reduces mortality in septic mice.

Clinical Implications

Suggests therapeutic strategies targeting platelet adhesion/activation, mast cell activation, or chymase to prevent shock; supports biomarker development linking platelet dynamics and mast cell activation.

Limitations

• Predominantly murine; translational efficacy and safety of chymase inhibition need clinical testing
• The relative contribution of PAF versus other mediators may vary across sepsis etiologies

Future Directions

Early-phase trials of chymase inhibitors and strategies modulating platelet–mast cell interactions; development of biomarkers for mast cell activation in septic patients.