Activated Protein C Decreases Alveolar Protein Leakage in an Animal Model of Ventilator-Induced Lung Injury

Background: Mechanical ventilation with high tidal volumes can damage the alveolar-capillary barrier and activate a local and systemic inflammation. Objectives: We investigate the effects of activated protein C (APC) on gas exchange, lung cytokine and protein leakage, and systemic fibrinolytic activity in a rat model of ventilator-induced lung injury (VILI).Methods: Male Sprague-Dawley rats were ventilated with a high-volume zero positive end-expiratory pressure (PEEP) (HVZP) protocol by a volume-cycled ventilator for 2 h at a tidal volume of 30 mL/kg, a respiratory rate of 40 breaths/min, and an FiO2 of 0.21. Fifty minutes before ventilation, the rats received either intravenous APC (500 μg/kg, HVZP + APC group) or normal saline (vehicle for APC; HVZP group). Another group that received no ventilation served as the control.Results: The arterial blood gas tensions were comparable among three study groups before mechanical ventilation. Rats treated with HVZP ventilation exhibited higher mean pH and lower mean carbon dioxide tension than control animals and the arterial blood gas tensions were comparable between HVZP and HVZP + APC groups throughout the study period. HVZP group exhibited significantly higher bronchoalveolar lavage fluid (BALF) protein and plasma D-dimer than did the control group and APC treatment significantly reduced these increments. BALF MIP-2 was significantly higher in rats ventilated with HVZP ventilation than in control animals. HVZP and HVZP + APC groups had a significantly higher lung PAI-1mRNA expression and plasma active PAI-1 level than did the control group.Conclusions: High tidal volume and no PEEP ventilation increase lung alveolar protein leakage, which is attenuated by APC treatment.