HMGB1异常调控肺干细胞增殖分化在IPF发病中的作用及机制研究

特发性肺纤维化（IPF）发病机制的核心问题是损伤的功能性肺上皮细胞的再生障碍以及异常的纤维化修复。业已证实，肺干细胞在损伤后肺的再生修复中发挥了关键作用，然而这群肺干细胞在IPF发病中的作用及机制尚不清楚。我们前期研究发现IPF病人的肺上皮前体细胞大量减少，间质前体细胞相对增多，而进一步发现HMGB1是链接纤维化过程中炎症损伤-异常修复的关键桥梁分子,其介导的异常免疫微环境是IPF发病的核心事件。基于此我们提出假说：IPF发病过程中，肺损伤介导HMGB1的释放，通过与相应受体结合，活化了下游ERK1/2、AKT、STAT3、Wnt信号，进而导致c-kit+肺干细胞无法向正常终末肺泡结构分化，转而向效应成纤维细胞或肌纤维母细胞的异常分化。这可能是IPF发病的关键机制。深入探讨IPF过程中肺干细胞的异常分化及机理，有望为阐明肺纤维化的发生机制，开发有效治疗策略提供新思路。

The central mechanism of idiopathic pulmonary fibrosis (IPF) is deficiencies in regeneration of normal alveolar structure and aberrant lung repair with fibroblast activation. Lung stem cell has been proved to play a crucial role in the regeneration of lung after injury. However, the function and mechanisms of lung stem cell involved in the pathogenesis of IPF are still unclear. Our group have recently reported that there was a dramatic reduction of epithelial progenitor cells and a relative increase of the mesenchymal progenitor cells in IPF patients. In addition, we found high mobility group box 1(HMGB1) was a causal link between lung injury and abnormal repair in the pathogenesis of IPF,and the niches caused by HMGB1 could be a key issue of IPF. Based on these findings, we hypothesis that HMGB1,released by damaged lung, binds to related receptors,then activates downstream signaling pathway(ERK1/2, AKT、STAT3, Wnt), eventually drives c-kit+ lung stem cell away from terminal differentiation conducive to local alveolar tissue regeneration, towards effector fibroblast/myofibroblast development. These strategies based on investigation of the altered differentiation and role of lung stem cell in IPF may hold promise for illustrating the mechanism and developing novel treatment approaches for pulmonary fibrosis.