title: CD36 and Fyn kinase mediate malaria-induced lung endothelial barrier dysfunction in mice infected with Plasmodium berghei.
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.
authors: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors: Ifeanyi U
authors: IU
authors: Anidi
authors: Laura E
authors: LE
authors: Servinsky
authors: Otgonchimeg
authors: O
authors: Rentsendorj
authors: R Scott
authors: RS
authors: Stephens
authors: Alan L
authors: AL
authors: Scott
authors: David B
authors: DB
authors: Pearse
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015824:Blood-Air Barrier / Q000378:metabolism* / Q000503:physiopathology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D055785:Gene Knockdown Techniques; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008288:Malaria / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D010962:Plasmodium berghei; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018955:CD36 Antigens; D017382:Reactive Oxygen Species; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn
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