Abstract
Severe malaria can trigger acute lung injury characterized by pulmonary edema resulting from increased endothelial permeability. However, the mechanism through which lung fluid conductance is altered during malaria remains unclear. To define the role that the scavenger receptor CD36 may play in mediating this response, C57BL/6J (WT) and CD36−/− mice were infected with P. berghei ANKA and monitored for changes in pulmonary endothelial barrier function employing an isolated perfused lung system. WT lungs demonstrated a >10-fold increase in two measures of paracellular fluid conductance and a decrease in the albumin reflection coefficient (σalb) compared to control lungs indicating a loss of barrier function. In contrast, malaria-infected CD36−/− mice had near normal fluid conductance but a similar reduction in σalb. In WT mice, lung sequestered iRBCs demonstrated production of reactive oxygen species (ROS). To determine whether knockout of CD36 could protect against ROS-induced endothelial barrier dysfunction, mouse lung microvascular endothelial monolayers (MLMVEC) from WT and CD36−/− mice were exposed to H2O2. Unlike WT monolayers, which showed dose-dependent decreases in transendothelial electrical resistance (TER) from H2O2 indicating loss of barrier function, CD36−/− MLMVEC demonstrated dose-dependent increases in TER. The differences between responses in WT and CD36−/− endothelial cells correlated with important differences in the intracellular compartmentalization of the CD36-associated Fyn kinase. Malaria infection increased total lung Fyn levels in CD36−/− lungs compared to WT, but this increase was due to elevated production of the inactive form of Fyn further suggesting a dysregulation of Fyn-mediated signaling. The importance of Fyn in CD36-dependent endothelial signaling was confirmed using in vitro Fyn knockdown as well as Fyn−/− mice, which were also protected from H2O2- and malaria-induced lung endothelial leak, respectively. Our results demonstrate that CD36 and Fyn kinase are critical mediators of the increased lung endothelial fluid conductance caused by malaria infection.
Highlights
Severe malaria, a major source of morbidity and mortality in the developing world, is frequently complicated by acute respiratory distress syndrome (ARDS) which is characterized by increased vascular permeability resulting in pulmonary edema [1]
At day 6 post-infection, WT animals had histologic evidence of lung injury characterized by thickened alveolar septae, patchy alveolar edema and increased inflammatory cell infiltration, while the lungs from CD362/2 animals were indistinguishable from the lungs of uninfected controls (Figure 1A and 1B)
These results are consistent with previous reports that CD36 is a determinant of infected red blood cell (iRBC) adherence in the lungs [10] and with the hypothesis that CD36-dependent iRBCendothelial cell interactions contribute to pulmonary pathology during malaria
Summary
A major source of morbidity and mortality in the developing world, is frequently complicated by acute respiratory distress syndrome (ARDS) which is characterized by increased vascular permeability resulting in pulmonary edema [1]. The etiological agents of human malaria are vector-borne protozoan parasites that initially infect liver cells but rapidly develop to invade and reproduce in host erythrocytes These blood-stage parasites produce a number of proteins that are exported to the surface of the infected red blood cell (iRBC) [3]. The ability to sequester in the vasculature of certain tissues is thought to be advantageous to the parasite because it diminishes clearance of trophozoite- and schizont-containing iRBCs in the spleen and promotes factors that are beneficial for parasite growth [3,9] Sequestration in organs such as the lung is not without consequences, as large numbers of iRBCs in the lung have been hypothesized to precipitate events that result in lung injury [1]
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