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 StoleriuMichael Lindner, Anne Hilgendorff, Heiko Adler, Hans Günther Machens, Herbert B. Schiller, Stefanie M. Hauck, Yuval Rinkevich

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number173
JournalNature Communications
Volume16
Issue number1
DOIs
StatePublished - Dec 2025

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