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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/L1002    most recent 90555.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Finigan, J. H. Articles by Hassoun, P. M. PubMed PubMed Citation Articles by Finigan, J. H. Articles by Hassoun, P. M.

Activated protein C protects against ventilator-induced pulmonary capillary leak

¹Division of Pulmonary and Critical Care Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio; ²Johns Hopkins University School of Medicine, ³Division of Physiology, Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, and ⁴Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland; ⁵Howard Hughes Medical Institute, Oklahoma Medical Research Foundation, Departments of Biochemistry and Molecular Biology and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and ⁶Department of Medicine, University of Chicago Pritzker School of Medicine, Chicago, Illinois

Submitted 12 November 2008 ; accepted in final form 6 April 2009

The coagulation system is central to the pathophysiology of acute lung injury. We have previously demonstrated that the anticoagulant activated protein C (APC) prevents increased endothelial permeability in response to edemagenic agonists in endothelial cells and that this protection is dependent on the endothelial protein C receptor (EPCR). We currently investigate the effect of APC in a mouse model of ventilator-induced lung injury (VILI). C57BL/6J mice received spontaneous ventilation (control) or mechanical ventilation (MV) with high (HV_T; 20 ml/kg) or low (LV_T; 7 ml/kg) tidal volumes for 2 h and were pretreated with APC or vehicle via jugular vein 1 h before MV. In separate experiments, mice were ventilated for 4 h and received APC 30 and 150 min after starting MV. Indices of capillary leakage included bronchoalveolar lavage (BAL) total protein and Evans blue dye (EBD) assay. Changes in pulmonary EPCR protein and Rho-associated kinase (ROCK) were assessed using SDS-PAGE. Thrombin generation was measured via plasma thrombin-antithrombin complexes. HV_T induced pulmonary capillary leakage, as evidenced by significant increases in BAL protein and EBD extravasation, without significantly increasing thrombin production. HV_T also caused significant decreases in pulmonary, membrane-bound EPCR protein levels and increases in pulmonary ROCK-1. APC treatment significantly decreased pulmonary leakage induced by MV when given either before or after initiation of MV. Protection from capillary leakage was associated with restoration of EPCR protein expression and attenuation of ROCK-1 expression. In addition, mice overexpressing EPCR on the pulmonary endothelium were protected from HV_T-mediated injury. Finally, gene microarray analysis demonstrated that APC significantly altered the expression of genes relevant to vascular permeability at the ontology (e.g., blood vessel development) and specific gene (e.g., MAPK-associated kinase 2 and integrin-β₆) levels. These findings indicate that APC is barrier-protective in VILI and that EPCR is a critical participant in APC-mediated protection.

endothelial protein C receptor; mechanical stress; vascular barrier function; ventilator-induced lung injury