Fischer Adrian, Han Wei, Hu Shaoping, Mück-Häusl Martin, 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, Lindner Michael, Hilgendorff Anne, Adler Heiko, Machens Hans-Günther, Schiller Herbert B, Hauck Stefanie M, Rinkevich Yuval
Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München, Neuherberg, Germany.
Institute of Regenerative Biology and Medicine(IRBM), Helmholtz Zentrum München, Munich, Germany.
Nat Commun. 2025 Jan 2;16(1):173. doi: 10.1038/s41467-024-55596-x.
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.
肺纤维化的发展涉及肺泡巨噬细胞，但其机制尚未完全明确。在此，我们对小鼠肺纤维化过程中的结缔组织进行了谱系追踪，观察到结缔组织大分子从胸膜-肺泡连接处（PAJ）分解并转移至肺深部组织，从而激活成纤维细胞并引发纤维化。PAJ大分子向肺深部组织的分解和转移是由肺泡巨噬细胞介导的，其通过激活胸膜间皮上的半胱氨酸型蛋白水解作用来实现。PAJ生态位和分解级联反应在患者肺活检组织中活跃，在慢性纤维化模型中持续存在，而在急性纤维化模型中则减弱。携带半胱氨酸蛋白酶抑制剂胱抑素A的胸膜特异性病毒疗法可阻断PAJ分解，逆转纤维化并使慢性纤维化肺再生。通过靶向胸膜来靶向PAJ分解可能为治疗肺纤维化疾病提供一条独特的治疗途径。
