Modeling Mechanical Activation of Macrophages During Pulmonary Fibrogenesis for Targeted Anti-Fibrosis Therapy.
Modeling Mechanical Activation of Macrophages During Pulmonary Fibrogenesis for Targeted Anti-Fibrosis Therapy.
复制标题
模拟肺纤维化过程中巨噬细胞的机械激活，用于靶向抗纤维化治疗。
DOI：
10.1101/2023.07.19.549794
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Zhao,Ruogang
中科院分区：
文献类型：
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作者：
Xu,Ying;Ying,Linxuan;Lang,JenniferK;Hinz,Boris;Zhao,Ruogang
肺纤维化通常是一种致命的肺部疾病。免疫细胞如巨噬细胞被证明在纤维化肺中积聚，但它们对纤维化发展的贡献尚不清楚。为了概括巨噬细胞在肺纤维化发展中的作用，我们建立了一个人类巨噬细胞和成纤维细胞共培养的纤维化微组织模型。我们发现，在地形控制的基质组织上播种的纤维化巨噬细胞被机械激活。由此产生的巨噬细胞、胶原纤维和成纤维细胞的共同排列促进了微工程肺组织中广泛的纤维形成。使用吡非尼酮进行抗纤维化治疗可破坏纤维化巨噬细胞的极化和机械活化，导致纤维化抑制。吡非尼酮通过抑制整合素αMβ2和rho相关激酶2抑制巨噬细胞的机械活化。这些结果证明了巨噬细胞在组织水平上潜在的肺纤维化机制。共培养微组织模型是研究免疫-间质细胞相互作用和抗纤维化药物机制的有力工具。
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.