Endothelial Biomarkers and the Pathogenesis of Cerebral Malaria

Abstract

Cerebral malaria occurs due to abnormality in the function of the brain endothelium. This signifies that the brain endothelium plays a crucial role in the outcome of malaria in children. Regulated balance between angiopoietin-1 and angiopoeitin-2 is responsible for the control of normal endothelial cell function. The angiopoietin-Tie-2 system has been shown to regulate endothelial cell function and vascular integrity. Endothelial Protein C Receptor (EPCR) and Thrombomodulin (TM) are receptors on the endothelium and are required for the activated protein C cellular pathway which is known to have some microvascular protective effects. Elevated serum or plasma TM and EPCR levels suggested to be due to endothelial damage have been shown to be found in diseases associated with systemic or locally increased levels of inflammatory cytokines such as malaria. The study aimed to investigate the relationship between Ang-1, Ang-2, sEPCR and sTM and the pathogenesis of P. falciparum malaria infection in children with circulating endothelial progenitor cells and circulating endothelial cells which are known to be responsible for endothelial repair when damage occurs. Children between the ages of 2 to 12 years presenting with CM or UM were recruited from 5 hospitals in Accra and healthy children within the same age range were also recruited as controls. In addition to clinical and haematological determinations, levels of Ang-1, Ang-2, sEPCR and sTM in the plasma of all subjects were measured using ELISA. It was found that Ang-1 levels were higher in the healthy children compared to children who had uncomplicated or cerebral malaria and was associated with immature EPC levels (P < 0.05). It was also found that soluble TM was highest in children in the cerebral malaria group compared to uncomplicated malaria and healthy control groups (P < 0.05). The study suggests that Ang-1 but not Ang-2 is a predictor of endothelial damage and EPC recruitment. Also sTM was found to be a predictor of endothelial damage.