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Am J Respir Cell Mol Biol. 2017 Nov;57(5):589-602. doi: 10.1165/rcmb.2016-0358OC.

Restoration of Megalin-Mediated Clearance of Alveolar Protein as a Novel Therapeutic Approach for Acute Lung Injury.

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1 Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany.
2 Department of Pediatrics, University of Colorado at Denver, Aurora, Colorado.
3 Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; and.
4 Organ Protection Program, Department of Anesthesiology, University of Colorado at Denver, Aurora, Colorado.


Acute respiratory distress syndrome constitutes a significant disease burden with regard to both morbidity and mortality. Current therapies are mostly supportive and do not address the underlying pathophysiologic mechanisms. Removal of protein-rich alveolar edema-a clinical hallmark of acute respiratory distress syndrome-is critical for survival. Here, we describe a transforming growth factor (TGF)-β-triggered mechanism, in which megalin, the primary mediator of alveolar protein transport, is negatively regulated by glycogen synthase kinase (GSK) 3β, with protein phosphatase 1 and nuclear inhibitor of protein phosphatase 1 being involved in the signaling cascade. Inhibition of GSK3β rescued transepithelial protein clearance in primary alveolar epithelial cells after TGF-β treatment. Moreover, in a bleomycin-based model of acute lung injury, megalin+/- animals (the megalin-/- variant is lethal due to postnatal respiratory failure) showed a marked increase in intra-alveolar protein and more severe lung injury compared with wild-type littermates. In contrast, wild-type mice treated with the clinically relevant GSK3β inhibitors, tideglusib and valproate, exhibited significantly decreased alveolar protein concentrations, which was associated with improved lung function and histopathology. Together, we discovered that the TGF-β-GSK3β-megalin axis is centrally involved in disturbances of alveolar protein clearance in acute lung injury and provide preclinical evidence for therapeutic efficacy of GSK3β inhibition.


acute respiratory distress syndrome; alveolar epithelium; protein transport; pulmonary edema; transforming growth factor β

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