Abstract
The severity of Plasmodium falciparum malaria is associated with parasite cytoadherence, but there is limited knowledge about the effect of parasite cytoadherence in malaria-associated acute respiratory distress syndrome (ARDS). Our objective was to evaluate the cytoadherence of infected red blood cells (iRBCs) in a murine model of ARDS and to appraise a potential function of endothelial protein C receptor (EPCR) in ARDS pathogenesis. DBA/2 mice infected with P. berghei ANKA were classified as ARDS- or hyperparasitemia- (HP-) developing mice according to respiratory parameters and parasitemia. Lungs, blood, and bronchoalveolar lavage were collected for gene expression or protein analyses. Primary cultures of microvascular lung endothelial cells from DBA/2 mice were analyzed for iRBC interactions. Lungs from ARDS-developing mice showed evidence of iRBC accumulation along with an increase in EPCR and TNF concentrations. Furthermore, TNF increased iRBC adherence in vitro. Dexamethasone-treated infected mice showed low levels of TNF and EPCR mRNA expression and, finally, decreased vascular permeability, thus protecting mice from ARDS. In conclusion, we identified that increased iRBC cytoadherence in the lungs underlies malaria-associated ARDS in DBA/2-infected mice and that inflammation increased cytoadherence capacity, suggesting a participation of EPCR and a conceivable target for drug development.
Highlights
Malaria infection by Plasmodium falciparum is responsible for the largest number of severe and fatal diseases in the tropics [1, 2]
When they were perfused with 1 × PBS, the bioluminescence signal remained concentrated in the spleen and lungs and slightly in the liver especially in acute respiratory distress syndrome (ARDS)-developing mice (Figures 1(a)–1(c)), corroborating our published data where we showed more bioluminescence signal in ARDS mice compared to HP [14]
We found that ARDS-developing mice have approximately 28.5 times more endothelial protein C receptor (EPCR) expression than uninfected mice; they showed more EPCR protein in their lungs than HP-developing mice, and TNF-stimulated Primary microvascular lung endothelial cells (PMLECs) displayed an upregulation in EPCR expression compared to that of nonstimulated cells (NS) or cells stimulated with infected red blood cells (iRBCs), indicating that EPCR can contribute to ARDS progression
Summary
Malaria infection by Plasmodium falciparum is responsible for the largest number of severe and fatal diseases in the tropics [1, 2]. An important aspect of the pathogenesis of severe malaria results from the ability of infected red blood cells (iRBCs) to adhere to the microvasculature This interaction between iRBCs and the endothelium can cause blocking of blood flow and/or a local inflammatory response [3,4,5]. Murine models have been used to study malaria-associated ARDS [10, 11], and DBA/2 mice infected with P. berghei ANKA (PbA) develop ARDS and die between the 7th to 12th day postinfection (dpi) with pleural effusion, edema, and inflammatory infiltration in the lungs but without signals of cerebral malaria. We established predictive criteria to distinguish which mice would die from ARDS on the 7th dpi using respiratory and parasitemia data [12] Using this model, we found that on average 50% of the mice died from ARDS and 50% died from HP. VEGF is important in the PbAinfection of DBA/2 mice, this is not a universal effect, since the neutralization of VEGF receptor-2 did not decrease ARDS pathology in P. berghei NK65-infected C57BL/6 mice, another well-defined and accepted model of ARDS in malaria [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
