Targeting pleuro-alveolar junctions reverses lung fibrosis in mice.

Fischer, Adrian; Han, Wei; Hu, Shaoping; Häusl, Martin Mück; Wannemacher, Juliane; Kadri, Safwen; Lin, Yue; Dai, Ruoxuan; Christ, Simon; Su, Yiqun; Dasgupta, Bikram; Sardogan, Aydan; Deisenhofer, Christoph; Dutta, Subhasree; Kadri, Amal; Güney, Tankut Gökhan; Correa-Gallegos, Donovan; Mayr, Christoph H.; Hatz, Rudolf; Stoleriu, Mircea Gabriel

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. Lung fibrosis development involves alveolar macrophages, with mechanisms that are incompletely understood. Here, the authors show that alveolar macrophages mediate the disassembly of pleuro-alveolar junctions, driving fibrosis via connective tissue transfer, and demonstrate that targeting this process can reverse chronic fibrosis in mice.

PULMONARY fibrosis; ALVEOLAR macrophages; CYSTEINE proteinase inhibitors; MEDICAL sciences; CONNECTIVE tissues; LUNGS

Nature Communications, 2025, Vol 16, p1

2041-1723

Academic Journal

10.1038/s41467-024-55596-x