TY - JOUR
T1 - Targeting pleuro-alveolar junctions reverses lung fibrosis in mice
AU - Fischer, Adrian
AU - Han, Wei
AU - Hu, Shaoping
AU - Häusl, Martin Mück
AU - Wannemacher, Juliane
AU - Kadri, Safwen
AU - Lin, Yue
AU - Dai, Ruoxuan
AU - Christ, Simon
AU - Su, Yiqun
AU - Dasgupta, Bikram
AU - Sardogan, Aydan
AU - Deisenhofer, Christoph
AU - Dutta, Subhasree
AU - Kadri, Amal
AU - Güney, Tankut Gökhan
AU - Correa-Gallegos, Donovan
AU - Mayr, Christoph H.
AU - Hatz, Rudolf
AU - Stoleriu, Mircea Gabriel
AU - Lindner, Michael
AU - Hilgendorff, Anne
AU - Adler, Heiko
AU - Machens, Hans Günther
AU - Schiller, Herbert B.
AU - Hauck, Stefanie M.
AU - Rinkevich, Yuval
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85213941625&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-55596-x
DO - 10.1038/s41467-024-55596-x
M3 - Article
AN - SCOPUS:85213941625
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 173
ER -