New Hope for Pulmonary Fibrosis: Targeted Therapy Shows Regenerative Effects

In pulmonary fibrosis, scarring of the small air sacs in the lungs occurs, leading to progressive shortness of breath over time. The causes of pulmonary fibrosis are often unknown, and the disease manifests in various ways. Current therapies primarily focus on slowing disease progression, with the best-case scenario being the prevention of further scarring. However, reversing already existing tissue damage is usually not possible. This may now be about to change.

Researchers at the DZL site in Munich have discovered a promising new approach to treating pulmonary fibrosis and recently published their findings in Nature Communications. The study, titled "Targeting pleuro-alveolar junctions reverses lung fibrosis in mice", explores innovative strategies for treating pulmonary fibrosis. The research team investigated the role of the interface between the pleura (the lung lining) and alveoli (air sacs), known as the pleuro-alveolar junction (PAJ), in the development of pulmonary fibrosis.

The study reveals that during pulmonary fibrosis in mice, large macromolecules from connective tissue shift from the PAJs into deeper lung layers, where they activate fibroblasts and contribute to fibrosis. This process is mediated by alveolar macrophages, which trigger a specific type of protein breakdown, known as cysteine-type proteolysis, in the pleural mesothelium. Remarkably, this mechanism was observed not only in chronic fibrosis models in mice but also in lung biopsies from fibrosis patients.

A key finding of the study is that a pleura-specific viral therapy delivering the cysteine protease inhibitor Cystatin A not only halted these processes but also reversed fibrosis and promoted the regeneration of chronically fibrotic lungs. This approach opens up new therapeutic possibilities for treating pulmonary fibrosis by specifically targeting pleural structures.

These newly published findings represent a significant advancement in understanding and potentially treating pulmonary fibrosis. The results highlight the crucial role of pleural structures in disease progression and offer novel avenues for therapeutic intervention.

Original Publication: Fischer, A., Han, W., Hu, S. et al. Targeting pleuro-alveolar junctions reverses lung fibrosis in mice. Nat Commun 16, 173 (2025). https://doi.org/10.1038/s41467-024-55596-x