胸膜间皮细胞顶-底极性丢失在胸膜纤维化发生中的作用

Many respiratory diseases have remarkable pleural fibrosis, which is irreversible. So, figuring out the pathogenesis and finding out new therapeutic strategy of pleural fibrosis are urgent problems for researchers. Pleural mesothelial cell is the dominant cell type in pleura, which play a crucial role in the pathogenesis of pleural fibrosis. Research progress showed that: ①Pleural mesothelial cells contribute to the pathogenesis of pulmonary and pleural fibrosis through proliferation, migration and epithelial-mesenchymal transition (EMT); ②Change of epithelial apical-basal polarity attribute to the pathogenesis of carcinoma and fibrosis. Pleural mesothelial cell is a special type of epithelial cell, which share the feature of apical-basal polarity with epithelial cell. Our preliminary work showed that fibrotic factors induced loss of apical–basal polarity and EMT in pleural mesothelial cells. Therefore, we hypothesized that fibrotic factors induced loss of apical-basal polarity of pleural mesothelial cells contribute to the initiation and development of pleural fibrosis, maintain and re-build polarity at the early stage maybe a new therapeutic strategy for pleural fibrosis. We plan to confirm this hypothesis with in vitro, in vivo and clinical study. The aim of this project is to illustrate the pathogenesis of pleural fibrosis, and provide theoretical support for the prevention and treatment of pleural fibrosis.

许多呼吸系统疾病有明显的胸膜纤维化，胸膜纤维化一旦形成，难以逆转，迫切需要破解胸膜纤维化的发生机制并寻找新的治疗靶点。胸膜间皮细胞作为胸膜结构中最重要的细胞，在胸膜纤维化发生中的作用至关重要。研究进展提示①胸膜间皮细胞通过增殖、迁移及上皮-间充质转换(EMT)参与胸膜及肺纤维化的发生；②上皮细胞顶-底极性的改变参与肿瘤及纤维化疾病的发生。胸膜间皮细胞是特殊类型的上皮细胞，具有上皮细胞的顶-底极性。本项目的预实验发现了动物模型中胸膜间皮细胞顶-底极性的丢失，我们的前期工作已证实致纤维化因子可导致体外培养的胸膜间皮细胞顶-底极性丢失并诱导EMT的发生。因此，本项目拟利用细胞培养、整体动物及临床标本展开深入研究，以验证“致纤维化因子引起的胸膜间皮细胞顶-底极性丢失参与胸膜纤维化的发生、发展，早期维持和重建胸膜间皮细胞极性可减轻纤维化的发生”的创新性假说，项目的开展可为防治胸膜纤维化提供理论依据。

许多呼吸系统疾病有明显的胸膜纤维化表现，胸膜间皮细胞在胸膜纤维化的发生中扮演重要角色。因此，我们提出的假设：致纤维化因子引起的胸膜间皮细胞顶-底极性丢失参与胸膜纤维化的发生、发展，早期维持和重建胸膜间皮细胞极性可减轻纤维化的发生。我们既定的研究计划为：1致纤维化因子导致胸膜间皮细胞(PMC)顶-底极性丢失及分子机制；2 胸膜间皮细胞顶-底极性丢失在胸膜纤维化发病中的作用及其机制。主要研究结果为：1. 小鼠胸膜纤维化模型可见胸膜间皮细胞顶-底极性丢失；2. 博莱霉素导致胸膜间皮细胞极性的丢失；3. 博莱霉素改变PAR复合物中Lgl1和PAR-3A的量而影响胸膜间皮细胞极性；4 Lgl1 敲减可防止博莱霉素引起的PMC细胞极性丢失；5. Lgl1 敲减可防止TGF-β1引起的PMC细胞极性丢失；6. Lgl1基因敲除减轻博莱霉素加碳粉引起的小鼠胸膜纤维化。总之，我们发现，胸膜纤维化的发生过程中有PMC极性丢失，Lgl1的表达增加，与PAR-3A竞争结合PAR-6B，是导致极性丢失的分子机制。抑制Lgl1和维持PMC的细胞极性是胸膜纤维化治疗的潜在靶点。