Modeling mechanical activation of macrophages during pulmonary fibrogenesis for targeted anti-fibrosis therapy
Ying Xu1, Linxuan Ying1, Jennifer K Lang2
1Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
Abstract:
Pulmonary fibrosis is an often fatal lung disease. Immune cells such as macrophages were shown to accumulate in the fibrotic lung, but their contribution to the fibrosis development is unclear. To recapitulate the involvement of macrophages in the development of pulmonary fibrosis, we developed a fibrotic microtissue model with cocultured human macrophages and fibroblasts. We show that profibrotic macrophages seeded on topographically controlled stromal tissues became mechanically activated. The resulting co-alignment of macrophages, collagen fibers, and fibroblasts promoted widespread fibrogenesis in micro-engineered lung tissues. Anti-fibrosis treatment using pirfenidone disrupts the polarization and mechanical activation of profibrotic macrophages, leading to fibrosis inhibition. Pirfenidone inhibits the mechanical activation of macrophages by suppressing integrin αMβ2 and Rho-associated kinase 2. These results demonstrate a potential pulmonary fibrogenesis mechanism at the tissue level contributed by macrophages. The cocultured microtissue model is a powerful tool to study the immune-stromal cell interactions and the anti-fibrosis drug mechanism.
Insights
Profibrotic macrophages mechanically activate and promote lung fibrosis. Pirfenidone treatment inhibits this process by targeting specific macrophage pathways, offering a new therapeutic strategy for pulmonary fibrosis.
Area of Science:
- Immunology
- Biomedical Engineering
- Pulmonary Medicine
Background:
- Pulmonary fibrosis is a fatal lung disease.
- Macrophages accumulate in fibrotic lungs, but their role is unclear.
- Understanding immune cell involvement is crucial for developing treatments.
Purpose of the Study:
- To investigate the role of macrophages in pulmonary fibrosis development.
- To develop a microtissue model for studying immune-stromal interactions.
- To explore the mechanism of anti-fibrosis drug pirfenidone.
Main Methods:
- Co-cultured human macrophages and fibroblasts in a microtissue model.
- Utilized topographically controlled stromal tissues for macrophage seeding.
- Analyzed macrophage activation, cell alignment, and collagen deposition.
- Assessed pirfenidone's effect on macrophage polarization and signaling pathways.
Main Results:
- Profibrotic macrophages were mechanically activated on stromal tissues.
- Macrophage, collagen, and fibroblast co-alignment drove fibrogenesis.
- Pirfenidone disrupted macrophage polarization and mechanical activation.
- Pirfenidone suppressed integrin αMβ2 and Rho-associated kinase 2.
Conclusions:
- Macrophages contribute to pulmonary fibrogenesis at the tissue level.
- Macrophage mechanical activation is a key mechanism in fibrosis.
- The microtissue model effectively studies immune-stromal interactions and drug mechanisms.
- Pirfenidone shows potential for inhibiting pulmonary fibrosis by targeting macrophage activation.
