Nature Communications (Jan 2025)
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,
- Yuval Rinkevich
Affiliations
- Adrian Fischer
- Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München
- Wei Han
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Shaoping Hu
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Martin Mück Häusl
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Juliane Wannemacher
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Safwen Kadri
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Yue Lin
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Ruoxuan Dai
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Simon Christ
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Yiqun Su
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Bikram Dasgupta
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Aydan Sardogan
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Christoph Deisenhofer
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Subhasree Dutta
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Amal Kadri
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Tankut Gökhan Güney
- Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München
- Donovan Correa-Gallegos
- Institute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU Munich
- Christoph H. Mayr
- Helmholtz Munich, Research Unit for Precision Regenerative Medicine (PRM), 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
- Helmholtz Zentrum München, Institute of Lung Biology & Disease, Group Mechanism of Neonatal Chronic Lung Disease, Member of the German Center of Lung Research (DZL)
- Heiko Adler
- Member of the German Center of Lung Research (DZL)
- Hans-Günther Machens
- Department of Plastic and Hand Surgery, Technical University of Munich, School of Medicine and Health, Klinikum rechts der Isar
- Herbert B. Schiller
- Helmholtz Munich, Research Unit for Precision Regenerative Medicine (PRM), Member of the German Center for Lung Research (DZL)
- Stefanie M. Hauck
- Metabolomics and Proteomics Core, Helmholtz Zentrum München
- Yuval Rinkevich
- Institute of Regenerative Biology and Medicine, Chinese Institutes for Medical Research
- DOI
- https://doi.org/10.1038/s41467-024-55596-x
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 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.
