Alveolar fibrinolytic capacity is suppressed by injurious mechanical ventilation

Introduction:

Intra-alveolar fibrin depositions (i.e., hyaline membranes) are the histological hallmark of the neonatal respiratory distress syndrome (RDS) and acute lung injury (ALI). In ALI, they are the net result of a pro-coagulant milieu, dominated by inhibition of local fibrinolysis due to increased local production of plasminogen activator inhibitor (PAI)-1. Alveolar fibrin inactivates surfactant, leading to severe gas exchange disturbance. Although mandatory for most patients with RDS and ALI, mechanical ventilation causes lung damage by itself. We therefore investigated whether mechanical ventilation alters the fibrinolytic capacity of the lung, indicated by D-dimer (fibrin break down products) and PAI-1 in broncho-alveolar lavage fluids (BALF).

Methods and Measurements:

Sprague Dawley rats were connected to a ventilator and received intratracheal fibrinogen (40mg/kg)/thrombin (10µg/kg) instillations (intra-alveolar fibrin formation). They were then randomized to three ventilation groups: Group I (PIP16/PEEP 5cm H2O), Group II (PIP 26/PEEP 5cm H2O), Group III (PIP 36/PEEP 5cm H2O). Ten healthy rats served as controls.

After 3 hours of mechanical ventilation, lung weight (g)/ kg body weight (BW) (=relative lung weight) and concentrations of D-dimer and PAI-1 in BALF were measured.

Data are presented as mean±standard error (group II) and median±interquartile range (IQR) (groups I and III). A p<0.017 (one tailed) corrected for multiple comparisons was considered significant (ANOVA, Mann Whitney-U test).

Results:

D-dimer concentrations were highest in group I 187±23mg/L and decreased with increasing pressure amplitude: group II 93±20mg/L (p<0.001) and in group III 34±7mg/L (p<0.001). Inversely, concentrations of PAI-1 were undetectable in group I and increased with pressure amplitude: group II 0.55 U/mL (IQR 0; 4.3, p<0.001) and group III 3.05 U/mL (IQR 0; 4.4, p<0.001). PAI-1 levels correlated with increase in relative lung weight (Rsquare: 0.488, p<0.001).

Conclusion:

Alveolar fibrinolytic capacity was suppressed by injurious mechanical ventilation. This effect seemed to be PAI-1 dependent. PAI-1 production was correlated with ventilation-induced lung damage (relative lung weight). These findings provide new insights to the mechanisms involved in mechanical ventilation-induced lung injury.