Crosstalk between pleural mesothelial cell and lung fibroblast contributes to pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive and fibrosing interstitial pneumonia of unknown cause. The main feature of IPF is a heterogeneous appearance with areas of sub-pleural fibrosis. However, the mechanism of sub-pleural fibrosis was poorly understood. In this study, our in vivo study revealed that pleural mesothelial cells (PMCs) migrated into lung parenchyma and localized alongside lung fibroblasts in sub-pleural area in mouse pulmonary fibrosis. Our in vitro study displayed that cultured-PMCs-medium induced lung fibroblasts transforming into myofibroblast, cultured-fibroblasts-medium promoted mesothelial-mesenchymal transition of PMCs. Furthermore, these changes in lung fibroblasts and PMCs were prevented by blocking TGF-beta 1/Smad2/3 signaling with SB431542. TGF-beta 1 neutralized antibody attenuated bleomycin-induced pulmonary fibrosis. Similar to TGF-beta 1/Smad2/3 signaling, wnt/beta-catenin signaling was also activated in the process of PMCs crosstalk with lung fibroblasts. Moreover, inhibition of CD147 attenuated cultured-PMCs-medium induced collagen-I synthesis in lung fibroblasts. Blocking CD147 signaling also prevented bleomycin-induced pulmonary fibrosis. Our data indicated that crosstalk between PMC and lung fibroblast contributed to subpleural pulmonary fibrosis. TGF-beta 1, Wnt/beta-catenin and CD147 signaling was involved in the underling mechanism.

特发性肺纤维化（IPF）是一种病因不明的慢性、进行性、纤维化间质性肺炎的特殊形式。IPF的主要特征是具有胸膜下纤维化区域的异质性表现。然而，胸膜下纤维化的机制了解甚少。在本研究中，我们的体内研究显示，在小鼠肺纤维化中，胸膜间皮细胞（PMCs）迁移到肺实质，并在胸膜下区域与肺成纤维细胞相邻定位。我们的体外研究表明，培养的PMCs培养基诱导肺成纤维细胞转化为肌成纤维细胞，培养的成纤维细胞培养基促进PMCs的间皮 - 间质转化。此外，用SB431542阻断TGF -β1/Smad2/3信号通路可阻止肺成纤维细胞和PMCs的这些变化。TGF -β1中和抗体减轻了博来霉素诱导的肺纤维化。与TGF -β1/Smad2/3信号通路类似，Wnt/β - 连环蛋白信号通路在PMCs与肺成纤维细胞的相互作用过程中也被激活。此外，抑制CD147可减弱培养的PMCs培养基诱导的肺成纤维细胞中I型胶原合成。阻断CD147信号通路也可防止博来霉素诱导的肺纤维化。我们的数据表明，PMCs和肺成纤维细胞之间的相互作用导致了胸膜下肺纤维化。TGF -β1、Wnt/β - 连环蛋白和CD147信号通路参与了潜在机制。