Effects of activated protein C on ventilator-induced lung injury in rats.
BACKGROUND
Mechanical ventilation with a high tidal volume (VT) increases lung and systemic plasminogen activator inhibitor (PAI)-1 levels and alveolar fibrin deposition. Activated protein C (APC) may decrease PAI activity in endothelial cell-conditioned medium and thus enhance fibrinolysis.


OBJECTIVE
The aims of this study were to test the hypothesis that APC can neutralize PAI-1 activity and improve lung function in an animal model of ventilator-induced lung injury.


METHODS
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 VT of 30 ml/kg, a respiratory rate of 25 breaths/min, and an FiO(2) of 0.21. Fifteen minutes before ventilation, the rats received intravenous APC (250 microg/kg, HVZP+APC group) or normal saline (vehicle; HVZP group). Another group that received no ventilation served as the control group.


RESULTS
Levels of arterial blood gas tension were comparable between the two ventilation groups throughout the study period. Rats treated with the HVZP protocol exhibited significantly higher total protein and macrophage inflammatory protein-2 concentrations in bronchoalveolar lavage fluid (BALF) and higher lung PAI-1 mRNA expression and plasma active PAI-1 levels than did the control group. Administration of APC tended to reduce the BALF protein content and systemic PAI-1 activity but did not improve the lung histology in the HVZP+APC group. Plasma levels of D-dimers were comparable among the three study groups.


CONCLUSIONS
These results suggest that APC administered at a higher dosage might improve lung function by reducing alveolar protein leakage and systemic coagulation.
Jiang
Jiunn-Song
JS
Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital and School of Respiratory Therapy, Taipei, Taiwan, ROC.
Chou
Hsiu-Chu
HC
Wang
Leng-Fang
LF
Lang
Yaw-Dong
YD
Chen
Chung-Ming
CM
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D054426:Chemokine CXCL2 / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011486:Protein C / Q000494:pharmacology / Q000627:therapeutic use*; D011659:Pulmonary Gas Exchange; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013990:Tidal Volume; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D054426:Chemokine CXCL2; C513296:Cxcl2 protein, rat; D005338:Fibrin Fibrinogen Degradation Products; D017395:Plasminogen Activator Inhibitor 1; D011486:Protein C; D012333:RNA, Messenger; C036309:fibrin fragment D