Transcellular Mechanisms of Endothelial Permeability and Pulmonary Edema

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The transvascular exchange of fluid and solutes is an essential function of the pulmonary circulation required for the maintenance of lung tissue homeostasis. Increased lung endothelial permeability plays an important role in the pathogenesis of lung inflammatory states such as ARDS. A fundamental, but poorly understood, mechanism of endothelial transport involves the formation of vesicle carriers that transport plasma proteins, such as albumin. The overall objective of Project 1 is to define the nature of the transcellular pathway, its regulation, and its role in the mechanism of increased lung endothelial permeability. The proposed studies have the following specific aims: (i) Specific Aim #1: to determine (i) the segmental differences in the interactions of albumin with pulmonary vascular endothelial cells in vivo via the Albumin Binding Proteins (ABPs) and (ii) transcellular albumin transport in these segments; Specific Aim #2: to (i) determine the role of caveolin-1 in regulating pulmonary vascular endothelial barrier function (using CAV 1-/ mice and the siRNA strategy to suppress caveolin-1 expression in lung vascular endothelial cells) and (ii) establish the role of a described population of caveolin-1-independent vesicles in lung vascular endothelial transport; Specific Aim #3: to address the role of caveolin-1 in regulating pulmonary microvascular permeability via inter-endothelial junctions; and Specific Aim #4: to address the mechanisms of upregulation of caveolin- 1 induced by lipopolysaccharide and its consequences in increasing pulmonary vascular permeability via trannscytosis. Project 1 addresses the mechanisms by which albumin is transported through pulmonary vascular endothelial cells by a transcellular mechanism involving transcytosis under both normal conditions and after sepsis. Thus, Project 1 addresses the mechanisms by which albumin is transported through pulmonary vascular endothelial cells by a transcellular mechanism involving transcytosis under both normal conditions and after sepsis. Since the loss of pulmonary vascular endothelial barrier function is a key factor in the pathogenesis of lung inflammatory disease, such as ARDS, these studies will be important in defining the role of permeability pathways that contribute to protein-rich pulmonary edema. With an advanced understanding of these pathways, it will possible to specifically target these pathways and prevent the endothelial barrier disruption.