PI3K信号通路介导EMT过程对肺损伤的保护作用及机制

Airway inflammation and remodeling are the main pathogenesis and pathological feature of chronic lung injury. In the lung, alveolar epithelial type II cells are believed to serve as progenitors for repair of the alveolar epithelium following injury. Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an integral role in the process of repair and scar formation following epithelial injury in a number of tissues. PI3K signaling has been implicated in the control of a wide range of cellular activities such as proliferation, survival, adhesion, differentiation, cytoskeletal organization, etc. Several studies have reported that PI3K signal pathway play a role in EMT process in other tissues. Our previous study demonstrated that the intratracheal delivery of PI3K inhibitors could prevent from LPS-induced acute lung injury through the direct inhibitory effects on airway epithelial cells. Besides, We also found that PI3K signal pathway contribute to the chronic lung inflammation and airway remodeling. However, the mechanisms about how PI3K signal pathway involved in the alveolar EMT process is unclear. The present study will adopt:1)alveolar epithelial cell culture to observe the effects of PI3K on TGF-β induced EMT;2)siRNA technique to investigate the detailed regulation of PI3K signal pathway on alveolar EMT process;3)animal model to further confirm the effects of PI3K signal pathway on alveolar EMT process.Through the combination of in vivo and in vitro studies,we will comprehensively elucidate the possible mechanisms of PI3K pathway and EMT on lung inflammation and remodeling, thus provide new theory evidence for the treatment of lung injury.

在慢性肺损伤中，气道的炎症反应和重塑是其主要发病机制和病理特点。肺泡Ⅱ型上皮细胞-间充质细胞的转化过程EMT在肺组织的损伤修复过程中扮演重要角色。磷脂酰肌醇-3激酶PI3K是普遍存在于体内细胞的一类脂类激酶，已有研究证实PI3K抑制剂在其它组织的EMT过程中发挥作用。我们的前期研究结果已揭示抑制PI3K信号通路对不同因素所致的肺组织炎症反应、组织损伤以及气道重塑过程具有保护作用，但关于PI3K信号通路如何参与EMT过程来调控肺损伤修复的机制尚不明确。本研究采用1）肺泡上皮细胞模型观察PI3K信号通路对TGF-β所诱导的EMT过程的影响；2）小干扰RNA技术探讨PI3K信号通路对EMT过程的调控；3）通过动物模型进一步验证PI3K抑制剂对EMT过程的作用。结合体内外试验，全面探讨肺损伤过程中PI3K信号通路参与EMT过程进而调控肺组织炎症反应和组织重塑的机制，为肺损伤的治疗提供新的理论依据。

在慢性气道疾病中，气道的慢性炎症和重塑是其主要发病机制和病理特点。目前已有大量的研究证实肺泡II型上皮细胞-间充质细胞的转化过程（EMT）在肺组织的损伤修复过程中扮演重要角色。而转化生长因子-β（TGF-β）是EMT过程的主要诱发因子，它通过活化Smads等信号通路进而调节核内EMT相关转录因子的表达。我们前期研究结果已经揭示PI3K信号通路参与肺组织炎症反应、组织损伤以及气道重塑过程，PI3K抑制剂对多种因素所致的肺损伤的不同阶段具有保护作用，包括抑制急性期炎症反应、慢性期成纤维细胞活化和胶原沉积。本研究将进一步探讨PI3K信号通路参与肺损伤保护作用的机制，包括对EMT过程的调控及与经典EMT调控通路Smads信号通路之间的关系，探讨炎症反应和组织重塑过程的可能机制，为肺损伤的治疗提供新的理论依据。