IV胶原降解产物ac-PGP在肝肺综合征中的作用及其机制研究

In hepatopulmonary syndrome (HPS), the accumulation of the monocytes in the pulmonary microvascular is the key point. However, its pathogenesis remains unknown. In our previous study, we found that in the Common Bile Duct Ligation (CBDL) induced HPS rats, collagen type IV degraded in the pulmonary microvascular and the quantity of the degradation product (ac-PGP) increased. And thses induced monocytes accumulated in the pulmonary microvascular. Furthermore, all of these phenomenons were reversed and the HPS was getting better after the obstruction of the bile duct was relieved. We also found that ac-PGP improved the migration of the monocytes by the cellular experiment in vitro. Our data suggested that the degradation of the collagen type IV play an important role in the accumulation of the monocytes. Therefore, we will establish HPS rats model, using the experiments of Micro-CT, flow cytometry and mass spectrometry to demonstrate the role of the degradation of collagen type IV in recruitment of mononuclear cells in the pulmonary capillaries. This project may clarify a new mechanism for the accumulation of monocytes in HPS in the view of collagen type IV, which will provide us a new target of drug treatment on HPS intervention/prevention.

肺微血管内单核细胞聚集是肝肺综合征（Hepatopulmonary syndrome, HPS）发生发展的核心环节，但其具体机制尚不清楚。我们前期研究发现，在胆总管结扎（CBDL）诱发的大鼠HPS模型中肺微血管基底膜IV型胶原发生降解，而且其降解产物ac-PGP增加，肺微血管内单核细胞聚集；解除CBDL大鼠胆道梗阻后，上述现象逆转，HPS得以改善；体外细胞实验发现ac-PGP可促进单核细胞迁移，提示IV型胶原降解在HPS大鼠肺微血管内单核细胞聚集中发挥重要作用。本课题采用HPS大鼠模型，运用Micro-CT、流式细胞、质谱等技术，深入探讨肺内IV型胶原降解及其在HPS肺微血管内单核细胞聚集中的作用与机制。开展本研究，可望首次以IV型胶原降解为切入点诠释HPS肺微血管内单核细胞聚集的机制，为开发防治HPS的新药物干预靶点提供理论与实验基础。

肺微血管内单核细胞聚集是肝肺综合征（Hepatopulmonary syndrome, HPS）发生发展的核心环节，但其具体机制尚不清楚。我们前期研究发现，在胆总管结扎（CBDL）诱发的大鼠HPS模型中肺微血管基底膜IV型胶原发生降解，而且其降解产物ac-PGP增加，ac-PGP可促进单核细胞迁移，提示IV型胶原降解在HPS大鼠肺微血管内单核细胞聚集中发挥重要作用。在此基础上，我们通过系列研究证实大鼠HPS模型中ROS累积，促使IV型胶原降解为ac-PGP，进而募集单核细胞，诱导大鼠HPS模型中肺微血管生成与血管扩张，促进HPS进展。在此作用机制基础上，我们进一步通过药物清除大鼠HPS模型中ROS，显著抑制了胶原降解，抑制了肺内单核巨噬细胞聚集与血管生成，从而延缓了HPS进展。本课题不仅探讨了HPS肺微血管内单核细胞聚集的新机制，并在针对该作用机制进行新药开发，通过临床前实验验证了新药的应用潜力，同时印证了该作用机制在HPS进展过程中发挥了关键作用。