Journal article

Publication year: 2017

Pages: 589-602

Journal: American Journal of Respiratory Cell and Molecular Biology

Volume number: 57

Issue number: 5

ISSN: 1044-1549

eISSN: 1535-4989

Open access status: Green

DOI Link: https://doi.org/10.1165/rcmb.2016-0358OC

Publisher: American Thoracic Society

Abstract: 
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-alpha clinical hallmark of acute respiratory distress syndromeis critical for survival. Here, we describe a transforming growth factor (TGF)-beta-triggered mechanism, in which megalin, the primary mediator of alveolar protein transport, is negatively regulated by glycogen synthase kinase (GSK) 3 beta, with protein phosphatase 1 and nuclear inhibitor of protein phosphatase 1 being involved in the signaling cascade. Inhibition of GSK3 beta rescued transepithelial protein clearance in primary alveolar epithelial cells after TGF-beta 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 intraalveolar protein and more severe lung injury compared with wild-type littermates. In contrast, wild-type mice treated with the clinically relevant GSK3 beta 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-beta-GSK3 beta-megalin axis is centrally involved in disturbances of alveolar protein clearance in acute lung injury and provide preclinical evidence for therapeutic efficacy of GSK3 beta inhibition.

Harvard Citation style: Vohwinkel, C., Buchaeckert, Y., Al-Tamari, H., Mazzocchi, L., Eltzschig, H., Mayer, K., et al. (2017) Restoration of Megalin-Mediated Clearance of Alveolar Protein as a Novel Therapeutic Approach for Acute Lung Injury, American Journal of Respiratory Cell and Molecular Biology, 57(5), pp. 589-602. https://doi.org/10.1165/rcmb.2016-0358OC

APA Citation style: Vohwinkel, C., Buchaeckert, Y., Al-Tamari, H., Mazzocchi, L., Eltzschig, H., Mayer, K., Morty, R., Herold, S., Seeger, W., Pullamsetti, S., & Vadasz, I. (2017). Restoration of Megalin-Mediated Clearance of Alveolar Protein as a Novel Therapeutic Approach for Acute Lung Injury. American Journal of Respiratory Cell and Molecular Biology. 57(5), 589-602. https://doi.org/10.1165/rcmb.2016-0358OC