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Modeling mechanical activation of macrophages during pulmonary fibrogenesis for targeted anti-fibrosis therapy.

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.

SUBMITTER: Xu Y

PROVIDER: S-EPMC10980276 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Modeling mechanical activation of macrophages during pulmonary fibrogenesis for targeted anti-fibrosis therapy.

Xu Ying Y Ying Linxuan L Lang Jennifer K JK Hinz Boris B Zhao Ruogang R

Science advances 20240329 13

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 ...[more]

PMID: 38552026

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Project description:BackgroundIt is unclear whether continuing anti-fibrotic therapy until the time of lung transplant increases the risk of complications in patients with idiopathic pulmonary fibrosis.ObjectivesTo investigate whether the time between discontinuation of anti-fibrotic therapy and lung transplant in patients with idiopathic pulmonary fibrosis affects the risk of complications.MethodsWe assessed intra-operative and post-transplant complications among patients with idiopathic pulmonary fibrosis who underwent lung transplant and had been treated with nintedanib or pirfenidone continuously for ⩾ 90 days at listing. Patients were grouped according to whether they had a shorter (⩽ 5 medication half-lives) or longer (> 5 medication half-lives) time between discontinuation of anti-fibrotic medication and transplant. Five half-lives corresponded to 2 days for nintedanib and 1 day for pirfenidone.ResultsAmong patients taking nintedanib (n = 107) or pirfenidone (n = 190), 211 (71.0%) had discontinued anti-fibrotic therapy ⩽ 5 medication half-lives before transplant. Anastomotic and sternal dehiscence occurred only in this group (anastomotic: 11 patients [5.2%], p = 0.031 vs patients with longer time between discontinuation of anti-fibrotic medication and transplant; sternal: 12 patients [5.7%], p = 0.024). No differences were observed in surgical wound dehiscence, length of hospital stay, or survival to discharge between groups with a shorter versus longer time between discontinuation of anti-fibrotic therapy and transplant.ConclusionAnastomotic and sternal dehiscence only occurred in patients with idiopathic pulmonary fibrosis who discontinued anti-fibrotic therapy < 5 medication half-lives before transplant. The frequency of other intra-operative and post-transplant complications did not appear to differ depending on when anti-fibrotic therapy was discontinued.Registrationclinicaltrials.gov NCT04316780: https://clinicaltrials.gov/ct2/show/NCT04316780.

Dataset Information

Modeling mechanical activation of macrophages during pulmonary fibrogenesis for targeted anti-fibrosis therapy.

Publications

Modeling mechanical activation of macrophages during pulmonary fibrogenesis for targeted anti-fibrosis therapy.

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