Microparticle (MP) formation and matrix metalloproteinase (MMP) activation during ventilator induced lung injury (VILI)

Abstract

Ventilation with high peak inflation pressures (PIP) induces increased lung vascular permeability. Activation of MMP causes proteolytic breakdown of cell adhesion proteins and contributes to the increased permeability in VILI. MPs are membrane enclosed particles less than 1 micron diameter, produced by cell activation, exocytosis or apoptosis, and are known to produce endothelial cell dysfunction. To determine a possible link between MP and MMP activation, we ventilated C57/BL6 mice at 50 cmH2O PIP for 2 hours. Plasma MP numbers increased eightfold compared to unventilated controls while MP counts in BAL were similar. Using flow cytometry for surface proteins, 30% of plasma MP expressed CD31, CD54 and CD61, whereas approximately 50% expressed CD106, CD147, and E‐cadherin. In lungs ventilated with high PIP compared to low PIP (9 cmH2O), MMP‐2 activity increased 2‐fold in lung tissue and 25‐fold in BAL; MMP‐9 activity increased 2‐fold in lung tissue and 4‐fold in plasma, and tissue inhibitor of metalloproteinase (TIMP) decreased by 30% in lung tissue. Collagenase activity was approximately 2‐fold higher in MP compared to supernatant in both plasma and BAL. These data indicate that MP increased during VILI and possess surface proteins and MMP activity to bind to and degrade junctional proteins. MP may serve as targeted agents which contribute to increased vascular permeability during VILI. Supported by P01 HL66299.