许多间质性肺疾病有明显的胸膜及胸膜下病变，其发生机制是否与胸膜间皮细胞直接相关呢？近年有报道发现特发性肺纤维化病人的胸膜间皮细胞向肺内迁移，提示胸膜间皮细胞可能在间质性肺疾病的发生中起到非常关键的作用。同时，近年的研究进展证实"钙蛋白酶(calpain)诱导细胞迁移"、"calpain促进细胞外基质重建"。申请者的研究已经证实calpain参与肺血管重建，而且预实验提示"鼠肺纤维化中calpain介导胸膜间皮细胞肺内迁移且与纤维化病灶相关；体外培养中calpain介导胸膜间皮细胞增殖与迁移"。鉴于此，申请者拟进一步从分子、细胞及整体水平（包括利用calpain基因敲除小鼠）展开研究，以证实"胸膜间皮细胞在致病因子的作用下，由calpain介导，发生细胞增殖并向肺内迁移，参与细胞外基质重建，诱导胸膜及胸膜下纤维化发生"的创新性假说，为间质性肺疾病的防治探索新策略。

Pleural and subpleural disorders are very common in interstitial lung diseases (ILD). But the role of pleural mesothelial cells (PMCs) in the ILD was poorly understood. Mubarak et al reported parenchymal trafficking of PMCs in idiopathic pulmonary fibrosis which was published in European Respiratory Journal in 2012. The study suggested that PMCs should be very important in ILD, but more investigations are needed to reveal the detail mechanisms. In recent years, researchers revealed that calpain plays a pivotal role in regulating cell migration. Many factors inducing extracellular matrix remodeling via calpain was also confirmed recently. We previously found calpain mediated pulmonary arterial smooth muscle cells remodeling and pulmonary hypertension. In our preliminary experiments, we found PMCs migration into lung tissue via calpain in mice model of pulmonary fibrosis. In vitro, bleomycin inducing PMCs proliferation and migration through calpain was also confirmed. Taken together, we hypothesized that fibrotic factors induced increase in calpain activity, and then the activation of calpain induced PMCs proliferation and migration, as well as extracellular matrix remodeling, which is the key mechanism in pleural and subpleural fibrosis. In the project, we will do experiments using cell models and animal models, especially using calpain-4 knockout mice to confirm our hypothesis. The results of this project will be helpful for both understanding the mechanism and treating the disorders of fibrosis in ILD.