RhoA/ROCK通路调节osteopontin自分泌和旁分泌在肺纤维化发病中的作用

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease of unknown cause and poor prognosis. Recent evidence suggests that aggregation of lung fibroblasts plays an important role in the pathogenesis of IPF. Our previous study found that, administration of fasudil, a selective ROCK inhibitor, could attenuate bleomycin-induced pulmonary fibrosis in mice. Administration of fasudil can also reduce the ability of migration in NIH3T3 fibroblast cells. However, the detailed molecular mechanism of RhoA/ROCK pathway remains unclear. In the present study, in fibroblasts and cocultured macrophages, or in bleomycin-treated mice, we increase RhoA/ROCK levels by transgenic technology or decrease their levels by siRNA interference technology to examine autocrine and paracrine regulation of osteopontin, the migration ability of fibroblasts, and the development of pulmonary fibrosis. In summary, the study aims to investigate that there are complex interactions among RhoA/ROCK pathway, osteopontin and fibroblasts migration, which may modify the outcome of IPF therapy, and therefore should be considered for the rational design of anti-IPF strategy.

特发性肺纤维化发病机制不清，无有效治疗药物，预后差。成纤维细胞的肺部聚集被认为是IPF发生发展的重要环节。我们前期的研究发现，Rho激酶抑制剂可以显著降低博来霉素诱导小鼠肺泡炎和肺纤维化程度，在体外研究中能抑制成纤维细胞迁移，但RhoA/ROCK通路的具体作用机制还有待于进一步深入研究。本项目运用基因过表达和siRNA干扰技术干预RhoA/ROCK通路，调节成纤维细胞osteopontin自分泌和巨噬细胞/成纤维细胞共培养模型中巨噬细胞osteopontin旁分泌，观察其对成纤维细胞迁移的影响，并进一步在肺纤维化动物模型中观察干预RhoA/ROCK通路对osteopontin分泌、成纤维细胞迁移、肺纤维化发生发展的影响。本项目旨在探讨RhoA/ROCK通路、osteopontin分泌与成纤维细胞迁移、肺纤维化发病的关系，为可能的靶向治疗提供理论依据。