PMID:19363121

Citation	Finigan, JH, Boueiz, A, Wilkinson, E, Damico, R, Skirball, J, Pae, HH, Damarla, M, Hasan, E, Pearse, DB, Reddy, SP, Grigoryev, DN, Cheadle, C, Esmon, CT, Garcia, JG and Hassoun, PM (2009) Activated protein C protects against ventilator-induced pulmonary capillary leak. Am. J. Physiol. Lung Cell Mol. Physiol. 296:L1002-11
Abstract	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-beta(6)) levels. These findings indicate that APC is barrier-protective in VILI and that EPCR is a critical participant in APC-mediated protection.
Links	PubMed PMC2692806 Online version:10.1152/ajplung.90555.2008
Keywords	Acute Lung Injury/etiology; Acute Lung Injury/metabolism; Acute Lung Injury/physiopathology; Animals; Bronchoalveolar Lavage Fluid; Capillaries/metabolism; Capillary Permeability/physiology; Extravascular Lung Water/metabolism; Gene Expression/physiology; Glycoproteins/genetics; Glycoproteins/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Oligonucleotide Array Sequence Analysis; Protein C/genetics; Protein C/metabolism; Pulmonary Circulation/physiology; Pulmonary Edema/etiology; Pulmonary Edema/metabolism; Pulmonary Edema/physiopathology; Respiration, Artificial/adverse effects; Stress, Mechanical; rho-Associated Kinases/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:EPCR		GO:0043116 : negative regulation of vascular permeability	ECO:0000270:		P		Figure 6 demonstrates a decrease in vascular permeability when EPCR is overexpressed in the mice.	complete

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