Targeting pleuro-alveolar junctions reverses lung fibrosis in mice

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 and Yuval Rinkevich ()
Additional contact information
Adrian Fischer: Helmholtz Zentrum München
Wei Han: Helmholtz Zentrum München
Shaoping Hu: Helmholtz Zentrum München
Martin Mück-Häusl: Helmholtz Zentrum München
Juliane Wannemacher: Helmholtz Zentrum München
Safwen Kadri: Helmholtz Zentrum München
Yue Lin: Helmholtz Zentrum München
Ruoxuan Dai: Helmholtz Zentrum München
Simon Christ: Helmholtz Zentrum München
Yiqun Su: Helmholtz Zentrum München
Bikram Dasgupta: Helmholtz Zentrum München
Aydan Sardogan: Helmholtz Zentrum München
Christoph Deisenhofer: Helmholtz Zentrum München
Subhasree Dutta: Helmholtz Zentrum München
Amal Kadri: Helmholtz Zentrum München
Tankut Gökhan Güney: Helmholtz Zentrum München
Donovan Correa-Gallegos: LMU Munich
Christoph H. Mayr: Member of the German Center for Lung Research (DZL)
Rudolf Hatz: Asklepios Fachkliniken in Munich-Gauting
Mircea Gabriel Stoleriu: Asklepios Fachkliniken in Munich-Gauting
Michael Lindner: Asklepios Fachkliniken in Munich-Gauting
Anne Hilgendorff: Member of the German Center of Lung Research (DZL)
Heiko Adler: Member of the German Center of Lung Research (DZL)
Hans-Günther Machens: Klinikum rechts der Isar
Herbert B. Schiller: Member of the German Center for Lung Research (DZL)
Stefanie M. Hauck: Helmholtz Zentrum München
Yuval Rinkevich: Chinese Institutes for Medical Research

Nature Communications, 2025, vol. 16, issue 1, 1-18

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.

Date: 2025
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DOI: 10.1038/s41467-024-55596-x

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