Critical contribution of endothelial protein C receptor in experimental malaria-associated acute respiratory distress syndrome

Plasmodium falciparum malaria severity is associated with parasite cytoadherence, but limited knowledge about its effect in malaria-associated acute respiratory distress syndrome (ARDS) is notorious. Our objective was to evaluate cytoadherence of infected red blood cells (iRBC) in a murine model of ARDS and appraise the role of endothelial protein C receptor (EPCR) in ARDS pathogenesis. Lungs from ARDS-developing mice showed evidences of iRBC accumulation in lungs besides increase of EPCR and TNF concentrations. Furthermore, TNF increased iRBC adherence in vitro. Dexamethasone-treated infected mice showed lower levels of TNF and EPCR mRNA expression and, finally, decreased the vascular permeability, protecting mice from ARDS. In addition, EPCR knockdown decreased the capacity of iRBC adherence in vitro. In conclusion, we identified that increased iRBC cytoadherence in lungs underlies malaria-associated ARDS in DBA/2 infected mice and that inflammation increased cytoadherence capacity through EPCR expression suggesting a potential target for drug development.