Am J Respir Cell Mol Biol. 2017 Jul 5. doi: 10.1165/rcmb.2016-0358OC. [Epub ahead of print]
Restoration of Megalin-mediated Clearance of Alveolar Protein as a Novel Therapeutic Approach for Acute Lung Injury.
Acute respiratory distress syndrome (ARDS) 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 ARDS - is critical for survival and represents a promising target of therapeutic intervention. In this project, the authors describe for the first time a unique TGFβ-triggered and GSK3-mediated pathway that negatively regulates megalin, the major mediator of alveolar protein clearance. Inhibition of GSK3β rescued transepithelial protein clearance in primary alveolar epithelial cells after TGFβ treatment. Moreover, in a bleomycin-based model of acute lung injury, megalin heterozygous knock out animals showed a marked increase in intraalveolar protein and more severe lung injury compared to 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, the authors discovered that the TGFβ/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 in ARDS.