The acute respiratory distress syndrome (ARDS) displays mortality rates of up to 40 % in approximately 200,000 critically ill patients in the United States annually. The disease is characterized by accumulation of protein-rich edema in the alveolar space due to impaired endothelial and epithelial barrier function in the lung. Of great importance is the clearance of plasma proteins from the alveolar space. Sodium and fluid is cleared from the lung quite rapidly via active transport processes,

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... ding to increased protein concentration in the alveolar compartment. This increased concentration of protein creates an oncotic gradient which further promotes alveolar edema formation, thereby preventing recovery. Albumin clearance and edema resolution are crucial for the patient s survival. However, the mechanisms by which albumin transport is facilitated have not been fully elucidated. In the present study we used primary alveolar epithelial cells and an intact organ model to investigate the mechanisms of protein clearance from the alveolar space. In tight monolayers of alveolar epithelial type II cells and type I-like cells, transport of 125I-albumin was almost completely blocked by competition with unlabeled albumin. Similar results were obtained by assessing the uptake of FITC-albumin by fluorescence microscopy, indicating that albumin transport is facilitated by an active and receptor-mediated transport process. A number of previous studies have reported that clathrin-dependent endocytosis is the main pathway for protein uptake along epithelia, and the multi-ligand receptors megalin and cubilin have been established to facilitate clathrin-dependent endocytosis of proteins in the kidney. To investigate the role of clathrin-dependent endocytosis and megalin in the physiological significance of albumin transport in the lung, we applied receptor associated protein (RAP), an inhibitor of megalin-mediated endocytosis, to our cell monolayers and detected significantly decreased albumin transport rates. Since pharmacologica [...]