巨噬细胞外泌体circCRIM1通过FGF-2介导肺血管内皮细胞间充质转化调控机械通气相关性肺损伤的机制研究

机械通气相关性肺损伤(VILI)的机制尚未完全阐明，有研究显示FGF-2参与的肺血管内皮间充质转化在促进VILI中起到了重要作用。我们研究发现机械通气可以引起肺巨噬细胞外泌体中circCRIM1表达增加及肺组织中FGF-2表达上调，进一步研究发现circCRIM1竞争性抑制miR-503。结合文献报道miR-503的靶基因是FGF-2，据此申请人提出假说：机械通气引起肺巨噬细胞外泌体增加，外泌体进入肺血管内皮细胞中释放携带的circCRIM1竞争性抑制miR-503，上调FGF-2，从而促进了内皮细胞间充质转化导致机械通气相关性肺血管内皮损伤。为证实此假说，本研究拟采用基因修饰、实时荧光定量PCR等技术，利用体外与体内实验探讨巨噬细胞外泌体circCRIM1/miR-503/FGF-2通路影响肺血管内皮细胞间充质转化参与VILI的具体分子机制，为防治VILI提供新策略。

The mechanism of ventilation induced lung injury (VILI) has not been fully elucidated. Studies showed that FGF-2 invovled endothelial mesenchymal transition (EndMT) played an important role in promoting VILI. Our pre-experiments data showed that mechanical ventilation increased the expression of circCRIM1 in exosomes of pulmonary macrophages and up regulated the expression of FGF-2 in lung tissue. Our further studies found that circCRIM1 inhibited miR-503 competitively. Based on the literature reported that miR-503 regulated FGF-2 and our preliminary data, we proposed a hypothesis: mechanical ventilation increased the exosomes of pulmonary macrophages, the exosomes entered into pulmonary vascular endothelial cells to release circCRIM1, which competitively inhibited miR-503 and up regulated FGF-2, thus promoted the EndMT and caused pulmonary vascular endothelial injury of VILI. To prove this hypothesis, we use gene modification technology and quantitative real-time PCR to explore underlying molecular mechanism of macrophage exosomes circCRIM1/miR-503/FGF-2 pathway involving in EndMT associated VILI. This study will provide a new strategy for the prevention and treatment of VILI.