Targeting pleuro-alveolar junctions reverses lung fibrosis in mice
Abstract
Abstract Lung fibrosis development utilizes alveolar macrophages, with mechanisms that are incompletely understood. Here, we fate map connective tissue during mouse lung fibrosis and observe disassembly and transfer of connective tissue macromolecules from pleuro-alveolar junctions (PAJs) into deep lung tissue, to activate fibroblasts and fibrosis. Disassembly and transfer of PAJ macromolecules into deep lung tissue occurs by alveolar macrophages, activating cysteine-type proteolysis on pleural mesothelium. The PAJ niche and the disassembly cascade is active in patient lung biopsies, persists in chronic fibrosis models, and wanes down in acute fibrosis models. Pleural-specific viral therapeutic carrying the cysteine protease inhibitor Cystatin A shuts down PAJ disassembly, reverses fibrosis and regenerates chronic fibrotic lungs. Targeting PAJ disassembly by targeting the pleura may provide a unique therapeutic avenue to treat lung fibrotic diseases.
Article Details
Authors (27)
Adrian Fischer
Wei Han
Shaoping Hu
Martin Mück-Häusl
Juliane Wannemacher
Safwen Kadri
Yue Lin
Ruoxuan Dai
Simon Christ
Yiqun Su
Bikram Dasgupta
Aydan Sardogan
Christoph Deisenhofer
Subhasree Dutta
Amal Kadri
Tankut Gökhan Güney
Donovan Correa-Gallegos
Christoph H. Mayr
Rudolf Hatz
Mircea Gabriel Stoleriu
Michael Lindner
Anne Hilgendorff
Heiko Adler
Hans-Günther Machens
Herbert B. Schiller
Stefanie M. Hauck
Metabolomics and Proteomics Core, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.
Yuval Rinkevich