title: Megalin mediates transepithelial albumin clearance from the alveolar space of intact rabbit lungs.
abstract: The alveolo-capillary barrier is effectively impermeable to large solutes such as proteins. A hallmark of acute lung injury/acute respiratory distress syndrome is the accumulation of protein-rich oedema fluid in the distal airspaces. Excess protein must be cleared from the alveolar space for recovery; however, the mechanisms of protein clearance remain incompletely understood. In intact rabbit lungs 29.8 ± 2.2% of the radio-labelled alveolar albumin was transported to the vascular compartment at 37°C within 120 min, as assessed by real-time measurement of 125I-albumin clearance from the alveolar space. At 4°C or 22°C significantly lower albumin clearance (3.7 ± 0.4 or 16.2 ± 1.1%, respectively) was observed. Deposition of a 1000-fold molar excess of unlabelled albumin into the alveolar space or inhibition of cytoskeletal rearrangement or clathrin-dependent endocytosis largely inhibited the transport of 125I-albumin to the vasculature, while administration of unlabelled albumin to the vascular space had no effect on albumin clearance. Furthermore, albumin uptake capacity was measured as about 0.37 mg ml−1 in cultured rat lung epithelial monolayers, further highlighting the (patho)physiological relevance of active alveolar epithelial protein transport. Moreover, gene silencing and pharmacological inhibition of the multi-ligand receptor megalin resulted in significantly decreased albumin binding and uptake in monolayers of primary alveolar type II and type I-like and cultured lung epithelial cells. Our data indicate that clearance of albumin from the distal air spaces is facilitated by an active, high-capacity, megalin-mediated transport process across the alveolar epithelium. Further understanding of this mechanism is of clinical importance, since an inability to clear excess protein from the alveolar space is associated with poor outcome in patients with acute lung injury/acute respiratory distress syndrome.
authors: Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center, Klinikstrasse 33, 35392 Giessen, Germany
authors: Yasmin
authors: Y
authors: Buchäckert
authors: Sebastian
authors: S
authors: Rummel
authors: Christine U
authors: CU
authors: Vohwinkel
authors: Nieves M
authors: NM
authors: Gabrielli
authors: Benno A
authors: BA
authors: Grzesik
authors: Konstantin
authors: K
authors: Mayer
authors: Susanne
authors: S
authors: Herold
authors: Rory E
authors: RE
authors: Morty
authors: Werner
authors: W
authors: Seeger
authors: István
authors: I
authors: Vadász
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004705:Endocytosis; D004847:Epithelial Cells / Q000378:metabolism; D066298:In Vitro Techniques; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000494:pharmacology*
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D012710:Serum Albumin, Bovine