Endothelial Protein C Receptor Could Contribute to Experimental Malaria-Associated Acute Respiratory Distress Syndrome

Figure 6

Schematic representation of ARDS development involving adhesion of iRBCs to EPCR. Plasmodium berghei ANKA-infected red blood cells (iRBCs) induce TNF release by endothelial and inflammatory cells. TNF upregulates EPCR expression in lung endothelial cells, increasing iRBC adhesion in these cells through the EPCR pathway. The adhesion of iRBCs to lung endothelial cells leads to an increase in gap formation in the interendothelial junction, an increase in vascular permeability with infiltration of inflammatory cells and red blood cells, and edema formation. Activated alveolar macrophages also produce TNF, which contributes to the activation of endothelial cells, recruitment of neutrophils, and alveolar damage. Treatment with dexamethasone decreases inflammatory cytokine release, including TNF release and, consequently, downregulates EPCR expression in lung endothelial cells; dexamethasone also decreases VEGF released by endothelial cells, protecting mice from gap formations, vascular permeability, inflammatory cell infiltration, and alveolar damage.