激活迷走神经-α7 nAChR通路调控骨髓干(祖）细胞治疗急性肺损伤

尽管采用重症监护、限制液体和保护性机械通气技术，急性肺损伤（ALI）患者死亡率仍高达40%。实验表明骨髓间充质干细胞（MSC）和内皮祖细胞（EPC）对ALI有保护作用。MSC和EPC均表达α7 nAChR。通过活化α7 nACh可以增加干细胞对损伤组织的修复作用。我们发现激活迷走神经和α7 nAChR可以减轻酸吸入或E. coli诱发的ALI。然而，尚不清楚激活迷走神经和α7 nAChR能否调控骨髓干（祖）细胞对ALI的修复作用。本项目我们将应用分子生物学、免疫学、神经生理学等先进手段来研究：（1）激活迷走神经-α7 nAChR通路调动α7 nAChR+骨髓干（祖）细胞对ALI的修复作用；（2）阐明迷走神经-α7 nAChR通路通过AKT1、HIF-1α和CXCR4等信号分子参与α7 nAChR+骨髓干（祖）细胞动员、迁移、和修复ALI的分子机制。研究成果将为ALI提供新的治疗靶点。

Despite intensive care, fluid restriction, and protective mechanical ventilation, acute lung injury remains a mortality of 40%. Recent animal studies have demonstrated that administration of in vitro differentiated bone marrow mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC) could reduce pulmonary inflammation and improve survival of acute lung injury. Both MSC and EPC express α7 nicotinic acetylcholine receptor (α7 nAChR). In vitro, activation of α7 nAChR in MSC and EPC renders protective effects on injured cells. Our previous studies have shown that activation of vagus nerve-α7 nAChR pathway could attenuate acid aspration or E. coli-induced acute lung injury. However, whether vagus nerve through α7 nAChR could mobilize bone marrow stem (progenitor) cells, thereby affect the outcome of acute lung injury is unclear. In this project, we will take molecular biological, immunological, neurophysiological and other advanced apporoaches to study (i) whether activation of vagus nerve-α7 nAChR pathway would mobilize α7 nAChR-expressing bone marrow stem (progenitor) cells to repair acute lung injury; how vagus nerve-α7 nAChR pathway would utilize AKT1, HIF-1α, and CXCR4 to regulate mobilization and migration of α7 nAChR-expressing bone marrow stem (progenitor) cells for attenuating acute lung injury. Targeting α7 nAChR-expressing bone marrow stem (progenitor) cells might provide us novel avenue to reduce severity of acute lung injury.